Compounds and formulations suitable for radical scavenging

ABSTRACT

The present invention relates to compositions and methods of using free radical scavengers with reduced  1 O 2  generation. In certain embodiments, these compositions and methods of use relate to fullerene-derived ketolactams and fullerene-derived ketolactam derivatives, fullerene derivatives, and/or fullerenes. In yet other embodiments, the invention relates to cosmetic or dermatological compositions comprising said free radical scavengers with reduced  1 O 2  generation.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/516,992, now U.S. Pat. No. 8,580,810, issued Nov. 12, 2013, which isa §371 national stage application based on Patent Cooperation TreatyApplication serial number PCT/US2007/085879, filed Nov. 29, 2007, whichclaims the benefit of priority to U.S. Provisional Patent ApplicationSer. No. 60/861,697, filed Nov. 29, 2006; the entireties of all of whichare hereby incorporated by reference.

BACKGROUND OF THE INVENTION

It is well known in the art that fullerenes (such as, for example, C₆₀,C₇₀, C₇₆, C₇₈, and C₈₄), which are closed-cage all-carbon molecules, andchemical derivatives of fullerenes react with a wide variety of freeradical species (OH, NO., ROO., .aryl, .alkyl, etc.) and thus havepotential in various applications, including biological applications,where the reduction of free radical species, such as reactive oxygenspecies (ROS), is desired (Krusic, P. J. et al., Science, 254,1183-1185, 1991; Dugan, L. et al., Proc. Natl. Acad. Sci., 94,9434-9439, 1997; Lee, Y. T. et al., Proc. Soc. Exp. Bio. And Med., 224,69-75, 2000). ROS are known to contribute to cell damage and/or celldeath, as well as having a role in various metabolic and immune systemprocesses. Reduction in the concentration of one or more radical speciesin a biological environment thus has benefits in various biologicalenvironments for amelioration of a host of conditions. One example isthe reduction of OH., ROO. (peroxyl) and other radical speciesconcentrations around and in cell membranes so as to protect the cellmembrane and its components from oxidative damage, such as DNA cleavageand/or mutation, loss of cell wall integrity which can lead to death ofthe cell, or other undesired consequences of elevated concentrations ofROS. Another example is that supplementation with antioxidants may allowconservation of biological antioxidant compounds that occur naturally inhumans and animals, such as Vitamin E, Vitamin C, or others, which areconsumed by ROS. Such free radical scavengers or in the case where thefree radical species are oxidizing species, antioxidants (free radicalscavenger and antioxidant will be used interchangeably in the presentdocument), protection mechanisms occur naturally in biologicalenvironments through the activity of Vitamin E, Vitamin C, Coenzyme Q10,and other compounds, which react with free radical species, and gothrough various regeneration processes, reducing concentrations of freeradical species. In many cases it is desirable to augment thesenaturally occurring protection mechanisms through supplementation with afree radical scavenger.

Antioxidants have been shown to have efficacy in particular asprotectants and/or remediative agents in dermatological and cosmeticsapplications. Vitamin E, Vitamin C, Coenzyme Q10, naturally occurringantioxidants, such as polyphenolics derived from fruit seeds and skin(grape, cranberry, tomato, etc.), and synthetic compounds are usedextensively for the purpose of protection of the skin (human and animal)from oxidative stress caused by exposure to light, pollution, cigarettesmoke and other sources of free radicals, as well as endogenous sources,such as normal metabolic processes and immune system responses thatgenerate free radicals. Antioxidants are known as well as to promote thegeneral healthy appearance of the skin. Antioxidants also can play arole in the remediation of the appearance of inflammatory conditions ofthe skin, reduction in damage incurred to the skin by inflammation, andpromote the healing of inflammatory conditions of the skin, through thereduction of concentration of free radicals produced by the immunesystem, such as superoxide, nitric oxide, and hydrogen peroxide, forexample, caused by the respiratory burst of neutrophils in response tobacteria or other stimuli to the immune system.

The rate of formation of new extracellular matrix, such as collagen, inthe skin is also thought to be increased (or the process ofextracellular matrix breakdown is decreased) through the use of forexample Vitamin C and retinoid antioxidants, and the process of newextracellular matrix formation or conservation of extracellular matrixin the skin is enhanced through the use of antioxidants.

In addition antioxidants are taken as oral supplements to protectagainst oxidative damage or other consequences of ROS or other freeradicals to the skin and other biological substrates, such as neuronalcells, build-up of arterial plaque, prevention of cell apoptosis,inflammatory conditions, such as sepsis, and extension of life-span,among other uses. Conditions thought to be caused or exacerbated byexcess ROS and resulting oxidative damage include, but are not limitedto atherosclerosis, cancer, and neurological disorders, such asAlzheimer's disease and Parkinson's disease.

Commonly used antioxidant compounds as listed above, such as Vitamin E,Vitamin C, Coenzyme Q10, carotenoids, and plant derived polyphenols havevarious drawbacks, such as in some cases limited transport to andthrough biological environments, instability when exposed to light andair, and less than desired efficacy when applied as supplements. Onedrawback of many commonly used natural and synthetic antioxidants isthat they can in some cases have minimal efficacy or even havepro-oxidant activity due to the fact that they themselves become freeradicals after reacting with a free radical. This can lead to undesiredeffects, such as localized accumulation of the oxidized free radicalanalogues of the antioxidant and reaction with biological media, such ascells, if, for example, these antioxidants are not regenerated withcomplementary species (e.g., Vitamin E regenerated by Vitamin C).Vitamin E and other natural antioxidants must be regenerated viareaction with other antioxidants. Thus, supplementation with only one orseveral naturally occurring antioxidants may have reduced or littleefficacy, or even pro-oxidant activity in some cases since the entirereaction network necessary for recycling of the individual antioxidantsmay not be sufficient to regenerate the supplemented antioxidants. Itwould thus be desirable to provide an antioxidant supplement which didnot become a potentially reactive free radical species upon reactionwith free radicals.

Fullerenes are known to generate addition products with radicals thatare relatively stable and unreactive. The chemical reactivity offullerenes with free radicals is via addition reactions of the freeradicals with the C═C double bonds of the fullerene cage. Since multipleradicals can react with a single fullerene molecule (3, 6, 12, 16, ormore free radicals per fullerene molecule), it is possible that theradical electrons can pair and thus be neutralized. Fullerenes thus havevery desirable properties as free radical scavenging and antioxidantsupplements to biological systems.

A drawback however to the use of fullerenes as free radical scavengers,especially in protection of biological environments against ROS, is thewell-known property of fullerenes, especially C₆₀ and C₇₀, to producesinglet-oxygen, ¹O₂. Arbogast, J. W. et al., J. Phys. Chem., 95, 11,1991. This occurs via photoexcitation of the fullerene or fullerenederivative and generation of the excited triplet state which thentransfers energy to diatomic oxygen molecules to form ¹O₂ through theso-called Type 1 mechanism. It is also believed that the Type 2mechanism may occur for some fullerene compounds whereby electrons aretransferred to fullerenes and then to dissolved O₂, leading tosuperoxide anion (O₂ ⁻.). Yamakoshi, Y. et al., J. A. Chem. Soc., 125,42, 2003. In both cases the triplet excited state of the fullerene,which is in most cases relatively long-lived, is generated and leads tothe formation of either ¹O₂, O₂ ⁻., or other products. ¹O₂ and O₂ ⁻. arethemselves ROS that can lead to damage to biological substrates and arethus undesirable in the case where it is desired to reduce or minimizeconcentrations of ROS.

Triplet state and ¹O₂ quantum yields have been measured for native(underivatized) fullerenes and have been shown to be approximately 1.0for C₆₀, C₇₀, and C₇₈, and lower for C₇₆ and C₈₄ (between about 0.2 and0.3). Juha, L. et al., Chem. Phys. Lett., 335, 5, 539-544, 2001.Fullerene derivatives preserve this property to varying degrees, withmulti-substituted fullerene derivatives showing in some cases reduced¹O₂ generation capacity, though still significant. Hamano, T. et al.,Chem Commun. 21-22, 1997.

Ideally, a photosensitizer has good absorption in the visiblewavelengths combined with a high ¹O₂ quantum yield, among othercharacteristics. C₆₀ is not a very good absorber relative to commonlyused photosensitizers, such as methylene blue in the visiblewavelengths, but C₇₀, C₇₆, C₇₈, and C₈₄ are significantly betterabsorbers in the visible wavelengths, and this augments the overallphotosensitizing capacity. In the case of C₇₆ and C₈₄, this higher lightabsorption offsets the lower triplet state and ¹O₂ quantum yield interms of photosensitizing capacity. Therefore, even for the fullerenesC₇₆ and C₈₄, which have a lower singlet oxygen quantum yield compared toC₆₀ and C₇₀, it would be desirable to reduce the singlet oxygen quantumyield.

In many applications, especially biological applications, it would bedesirable to minimize the generation of ¹O₂ but preserve the inherentcapacity of the fullerene cage to react with free radicals, whilemaintaining a relatively low intrinsic optical absorption (i.e., molarextinction coefficient).

Fullerene-derived ketolactam derivatives of fullerenes (FIG. 1,Molecule 1) were first reported in 1995 by Hummelen et al. Hummelen, J.C. et al., J. Am. Chem. Soc., 117, 26, 1995.

Later it was shown that these fullerene-derived ketolactam compoundscould be used as intermediates to prepare (C₅₉N)₂ which in turn could beused as a precursor to prepare C₅₉NH and RC₅₉N azaheterofullerenederivatives. Hummelen, J. C. et al., Science, 269, 1554, 1995. Theimpetus for the preparation of these compounds was for application assuperconductors, organic ferromagnetism, and photoelectric components(n-type semiconductors in photodiodes). Ketolactams were also derivedfrom C₇₀, and in an analogous fashion, ketolactam derivatives offullerenes C₇₆, C₇₈, C₈₄ and other higher fullerenes can also beprepared. Hummelen, et al., Topics in Current Chemistry, SpringerVerlag, Vol. 199, 1999.

Tagmatarchis reported that (C₅₉N)₂ and C₅₉NH showed reduced ¹O₂ quantumyields and hypothesized that this was due to alteration of theelectronic structure of the fullerene cage by inclusion of the Nheteroatom in the fullerene cage. Tagmatarchis, N. et al., J. Org.Chem., 66, 8026-8029, 2001.

Hauke et al., further confirmed that a series of RC₅₉N compounds showedreduced ¹O₂ quantum yields. Hauke, F. et al., Chemistry, 12, 18,4813-4820, 2006. These compounds were prepared beginning with the(C₅₉N)₂ dimer synthesized with the keto-lactam intermediate. Hauke etal. showed through experimental measurements that the nature of the Rgroup significantly affected the ¹O₂ quantum yield, which for thecompounds with the lowest ¹O₂ quantum yield was about half the ¹O₂quantum yield of C₅₉NH, which is a significant change. No explanation isgiven for why the R group affects the triplet state and ¹O₂ quantumyields. Further, no consideration or conjecture on the triplet state and¹O₂ quantum yield properties of fullerene-derived ketolactams was given.

Other fullerene-derived ketolactam derivatives were later prepared foruse as n-type semiconductors in organic photovoltaics. Brabec, C. etal., Adv. Funct. Mater., 11, 5, 2001. None of the work withfullerene-derived ketolactams to date in the art has considered thetriplet state or ¹O₂ quantum yields of fullerene-derived ketolactams,nor envisioned the use of these compounds as free radical scavengers oras potentially generating less ¹O₂ than fullerenes and/or fullerenederivatives.

SUMMARY OF THE INVENTION

It is one object of the present invention to provide for afullerene-derived radical scavenger with reduced production of ¹O₂and/or other products resulting from the photogenerated triplet state offullerenes, while maintaining to a desirable degree the relatively lowoptical absorption properties and the ability for the fullerene-derivedmoiety to react with free radicals.

In some embodiments, these fullerene-derived radical scavengers arefullerene-derived ketolactams and fullerene-derived ketolactamderivatives. In certain embodiments, the fullerene-derived radicalscavengers may comprise one or more ketolactam modifications of thefullerene cage. Other embodiments may include the chemical bonding ofone or more addends to the fullerene cage, forming fullerene-derivedketolactam methano derivatives, fullerene-derived ketolactam pyrrolidinederivatives, fullerene-derived ketolactam epoxide derivatives,methanofullerene derivatives, pyrrolidine fullerene derivatives, orepoxide fullerene derivatives, or other fullerene-derived ketolactamderivatives or fullerene derivatives.

It is another object of the present invention to provide forformulations comprising antioxidants. In some embodiments, theseformulations may be used on the skin of an animal or human. In certainembodiments, these formulations may be used to reduce the concentrationof free radicals in the skin of an animal or human and/or to reduce thegeneration and/or concentration of singlet oxygen or superoxide in theskin of an animal or human. In certain embodiments, these formulationsmay be used to reduce the concentration of photoexcited triplet statesof fullerenes, fullerene derivatives, or fullerene-derived ketolactamsin the skin of an animal or human and/or to reduce the generation and/orconcentration of singlet oxygen or superoxide in the skin of an animalor human. In certain embodiments, the formulations may be used for thetreatment of inflammatory conditions, including acne, psoriasis, eczema,rosacea, sun-burn, allergic response, sepsis, dermatomyositis, radiationinduced erythema, chemically induced erythema, thermal burn, or laserinduced erythema. One of skill in the art would readily recognize thatother inflammatory conditions may be treated using the compounds andmethods of the present invention.

It is yet another object of the present invention to provide compoundsfor improving the stability of a formulation by reducing theconcentration of photoexcited triplet states of fullerenes, fullerenederivatives, or fullerene-derived ketolactams and/or reducing thegeneration and/or concentration of singlet oxygen or superoxide in aformulation containing a fullerene, fullerene derivative, orfullerene-derived ketolactam.

It is another object of the present invention to provide forformulations comprising fullerenes, fullerene derivatives, orfullerene-derived ketolactams which have a reduced propensity forphotooxidation by reduction in the optical transmittance of theformulation.

It is still another object of the present invention to provide compoundsfor use as semiconductors.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a fullerene-derived ketolactam (Molecule 1).

FIG. 2 depicts a general reaction scheme for the preparation offullerene-ketolactam compounds.

FIG. 3 depicts a common synthetic route for the preparation of azides.

FIG. 4 depicts one possible synthetic scheme for the compounds of thepresent invention.

FIG. 5 depicts examples of the UV-Vis spectra (measured against water)of various commercially available oils (an olive oil, a jojoba oil, anda grapeseed oil). Both a spectrum [a] for λ=350-800 nm and anenlargement [b] for the area between λ=500 and λ=600 nm is shown.

FIG. 6 depicts a spectrum (non-diluted, against H₂O) of amethanofullerene ([6,6]-phenyl C₆₁ butyric acid methyl ester, [60]PCBM,0.82 mg/10 mL), a fulleropyrrolidine(1′-Methyl-1′,5′-dihydro-2′-(3,5-didodecyloxyphenyl)-1H-pyrrolo[3′,4′:1,9](C60-Ih)[5,6]fullerene,F2C12, 2.11 mg/5 mL), and the ketolactam compound HG2-V2 (5.1 mg/10 mL)in grapeseed oil. See D. E Markov, et al., J. Phys. Chem. A, 109, 5266,2005.

FIG. 7 depicts the absorption of a 0.02% by weight mixture ofunderivatized fullerenes (a mixture of C₆₀/C₇₀/higher fullerenesapproximately in the molar proportion 70%/25%/5%) in grapeseed oil.

FIG. 8 depicts the spectrum of a concentrated solution of HG2-V2 ingrapeseed oil (9.2 mg HG2-V2 dissolved in 3 mL), diluted ten times (v/v)with toluene.

FIG. 9 depicts a synthesis of fullerene-derived ketolactam derivativeHG2-V 1.

FIG. 10 depicts fullerene-derived ketolactam HG2-V2.

FIG. 11 depicts the reaction of admantylideneadamantane (ad=ad) with ¹O₂to give a stable 1,2-dioxetane, adamantylideneadamantane peroxide. SeeWiering a, J. H. et al., Tetrahedron Letters, 2, 169, 1972.

FIG. 12 depicts a graph comparing singlet oxygen generation capacity ofPCBM and HGV2-V2.

FIG. 13 depicts the UV/Vis spectrum from an experiment to measure thegeneration of superoxide by HG2-V2.

FIG. 14 depicts fullerene-derived ketolactam KetoEster1.

FIG. 15 depicts one possible synthetic scheme for KetoEster1.

DETAILED DESCRIPTION OF THE INVENTION

One object of the present invention is to provide for afullerene-derived radical scavenger with reduced ¹O₂ and/or otherproducts resulting from the photogenerated triplet state of fullerenes,while maintaining to a desirable degree the relatively low opticalabsorption properties and the ability for the fullerene-derived moietyto react with free radicals. “Fullerene-derived ketolactam” refers to aketolactam molecule formed by cage-opening of a fullerene, as shown inFIG. 2. Fullerene-derived ketolactam molecules, as described herein, arenot termed fullerenes or fullerene derivatives, since the term“fullerene” refers to a close-caged, all carbon molecule, and the carboncage has been opened in the case of fullerene-derived ketolactams.

It has been found in the present work that C₆₀ fullerene-derivedketolactam derivatives have a capacity for generation of ¹O₂ which issignificantly less than C₆₀ and common C₆₀ derivatives, whilemaintaining a similar, low optical absorption profile, and thusfullerene-derived ketolactams are suitable for use in applications whereless generation of ¹O₂ is desirable than is possible with fullerenes orother fullerene derivatives. Since the majority of the fullerene cage isunmodified, the molecules of the present invention react with freeradicals with a desirable efficacy.

Certain compounds of the present invention are based on modification ofthe fullerene cage to give open-cage keto-lactams, with variousfunctional moieties to provide alterations in physical and chemicalproperties.

One general method for the preparation of fullerene-derived ketolactamsis by oxidation of [5,6]-azafulleroid derivatives (J. C. Hummelen etal., J. Am. Chem. Soc. 1995, 117, 7003). These latter compounds areobtained by addition of an azide derivative to a fullerene. Thisreaction is well known and a large variety of azafulleroids has beenprepared (A. Hirsch and M. Brettreich, Fullerenes: Chemistry andReactions. Wiley-VCH, 2005, Weinheim, Germany). The general reactionscheme is depicted in FIG. 2.

It has been demonstrated that functional groups, such as ether groupsand ester groups, can be present in the azide derivative used in theaddition reaction. The preparation of azide derivatives is well known inthe art, as is their reactivity. (See, for example: a) The chemistry ofthe azide group, S. Patai (Ed.), Wiley, New York, 1971; and b) Thechemistry of functional groups, Supplement D: the chemistry of halides,pseudo-halides and azides, S. Patai and R. Rappoport (eds.), J. Wileyand Sons, New York 1983.) A general scheme which can be used as aguideline for the preparation of the azide derivatives is depicted inFIG. 3. Protection of certain functional groups may be required in somecases

A common route for the synthesis of azides is by (nucleophilic)substitution of halogen atoms using sodium azide, as is demonstrated inthe synthesis of HG2-V1. A large variety of functional groups can bepresent in this substitution reaction without causing problems. However,other methods for the preparation of azides exist, the use of which canbe required if the substitution reaction leads to undesired sidereactions.

A large number of halogen-containing organic compounds are commerciallyavailable or can be easily prepared. The commercial compounds includederivatives, such as halogen-containing carboxylic acids,halogen-containing carboxylic esters, and halogen-containing alkyl-arylcompounds, all of which are suitable starting materials for thepreparation of the fullerene-ketolactams as described in the presentinvention. In addition, a large variety of alcohols are known inliterature or commercially available, which can be converted into thedesired halogen derivatives by various methods, such as by the reactionwith thionyl chloride, as is described in Example 1.

An example synthetic scheme for the compounds of the present inventionis outlined in FIG. 4. Azide compounds are reacted with C₆₀, and theresulting intermediate is then activated with light in the presence ofoxygen to convert the intermediate compound to the final open-cagefullerene-derived ketolactam compound, analogous to previously publishedsyntheses (C. J. Brabec et al., Advanced Functional Materials 2001, 11,374).

The wide selection available for the R group allows for the presentfullerene-derived ketolactam compounds to be chemically derivatized in awide variety to provide variations in chemical and physical properties,such as but not limited to solubility, bio-transport, and/or chemicalreactivity. The choice of different R addends may also providealterations in the triplet and ¹O₂ quantum yields, and may be chosen soas to optimize the triplet and ¹O₂ quantum yields and/or lightabsorption properties to alter the overall photosensitizing properties.

R-addends may be chosen that give additional reactivity, such as radicalscavenging ability, e.g., conjugated alkenes, such as carotenoids, orhydrogen-donating antioxidant moieties. Dyads may be created where theR-addend participates in electron transfer with the fullerenic moiety ofthe fullerene-derived ketolactam, e.g., porphyrin dyads may be prepared.

The fullerene-derived ketolactams of the present invention may also beprepared from C₇₀, C₇₆, C₇₈, C₈₄ or other fullerenes, by using theanalogous reaction chemistry as described here for C₆₀. Mixturescomprising two or more of the following: C₆₀-fullerene-derivedketolactam, C₇₀-fullerene-derived ketolactam, C₇₆-fullerene-derivedketolactam, C₇₈-fullerene-derived ketolactam, C₈₄-fullerene-derivedketolactam, and C₉₀-fullerene-derived ketolactam, may be synthesized byusing mixtures of the corresponding fullerenes in place of purefullerenes, and the resulting mixtures of fullerene-derived ketolactamsmay subsequently be used in any of the radical scavenging applications,such as skin care formulations, or other applications described herein.The different fullerenes or fullerene derivatives may be in anyproportion, but typically the composition (relative to fullerene-derivedketolactam content) would be 60%-90% of C₆₀-fullerene-derivedketolactam, 10%-40% C₇₀-fullerene-derived ketolactam, and 1%-20%fullerene-derived ketolactam based on fullerenes higher in molecularweight than C₆₀. See PCT/US07/72965 for descriptions of methods ofsynthesis of such mixtures.

In addition, mono-, bis-, or multi-adducts may be made which, inaddition to the ketolactam moiety, may consist of one or more otheraddends bonded directly to the fullerenic carbons. For example, Molecule2 (FIG. 4) may be used as a pre-cursor to the well-known diazoalkaneaddition chemistry (Hummelen, J. C. et al., J. Org. Chem., 60, 532-538,1995) to form an adduct consisting of Molecule 2 with an additionalphenyl-C_(n)-butyric-acid methyl-ester (PCBM) unit or othermethanofullerene unit attached in one or more locations of the sphericalfullerene moiety. In a similar fashion, so-called Prato adductsconsisting of pyrrolidine addends (Maggini, M. et al., J. Am. Chem.Soc., 115(21), 9798-9799, 1993) may be added in addition to theketolactam group. Further, epoxide adducts to the fullerene cage, formedby photochemical (Schuster, D. et al., Chem. Commun., 2493-2494, 1998)or other means, may be included in addition to the ketolactam group.Molecule 2 may be used as a precursor to synthesize the aforementionedmono-, bis-, or multi-adducts, or the methanofullerene, pyrrolidine orepoxide fullerene derivatives may be prepared and substituted for theC₆₀ reactant of FIG. 4. Further, the addition of one or more adducts tothe fullerene-derived ketolactams of the present invention can lead toeven further reduced capacity for generation of ¹O₂, since it has beenshown that with the increase of addends, such as epoxides to thefullerene core, the capacity for production of ¹O₂ decreases (Hamano, T.et al., Chem. Commun. 21-22, 1997).

In the case of fullerene epoxides, fullerene derivative epoxides, orfullerene-derived ketolactam epoxides (such as the mono-, bis-, ormulti-adduct compounds described above), it is also known that theepoxides are efficient quenchers of the fullerene, fullerene derivative,or fullerene-derived ketolactam photoexcited triplet state (Benedetto,A. F., Chemical Physics Letters, 310, 1999, 25-30), and data presentedherein shows that this leads to a net generation of singlet oxygen muchreduced from the expected values based on the quantum yield of singletoxygen generation for fullerenes and fullerene derivatives. Therefore,it is an object of the present invention to use epoxidized versions of afullerene, fullerene derivative, or fullerene-derived ketolactam, whichcan be prepared for example by the exposure of said fullerene, fullerenederivative, or fullerene-derived ketolactam to light and air, andincluded in a sufficient concentration to a formulation intended for usein skin care to preserve the formulation from photooxidation, and/or tominimize the formation of singlet oxygen and/or superoxide on or in theskin. Such epoxides of fullerenes, fullerene derivatives orfullerene-derived ketolactams, which act to quench photoexcited statesmay also be used to reduce the concentration of superoxide or singletoxygen directly via energy or electron transfer between the epoxidecompound and singlet oxygen or superoxide.

It is also envisioned that the addition of the ketolactam moietydirectly to the fullerene cage may give an advantage in the eventualbreakdown of the fullerene cage in metabolic and/or environmentalprocesses. Reaction with, for example, enzymes specific for keto- andlactam-groups may occur or other reactions with the additional keto- andlactam-oxygens, which may allow for easier degradation of the fullerenecage.

Addition of long-chain straight or branched alkane, conjugated alkene oralkene units, such as R═C₂₂H₄₅ or C₁₆H₃₃ (or alkoxy units, such asR═OC₂₂H₄₅ or R═OC₁₆H₃₃) are of interest for application in skincaresince they confer lipophilicity, which is desirable from the standpointof transport to and/or through the stratum corneum, and subsequentlocation in lipophilic regions of biological environments, such as cellwalls. Lipophilicity also allows convenient formulation in lipophilicingredients, such as oils, waxes, or wax-esters or other lipophiliccompounds which are commonly used in the art to create formulations forapplication to the skin. In some applications, for example in use as aninternal medication, more or less lipophilicity may be desired, orhydrophilicity may be desired. In the cases where hydrophilicity isdesired, glycolic or other polar units may be used as addends.

The compounds of the present invention are envisioned for use asantioxidants (or radical scavengers) in a range of applications whereantioxidants are commonly used, including but not limited to, skin care(cosmetic and dermatological), use as a pharmaceutical compound toameliorate or prevent conditions associated with oxidative stress, suchas but not limited to, neurological disorders, heart disease, disordersassociated with inflammation, etc. The compound of the present inventionmay also be used as antioxidants in non-health related uses, such aspolymer stabilizers, food preservatives, and the like.

The compound of the present invention are also envisioned for use toameliorate conditions associated with inflammation, such as caused bythe production of reactive oxygen species or other radical species bysuch immune system components as neutrophils. The compounds of thepresent invention, by scavenging such radical species produced by theimmune system, may thus mediate, prevent, or ameliorate immune systemresponses.

The compounds of the present invention may be used in topicalcompositions which also comprise a cosmetically and/or dermatologicallyacceptable carrier. The phrase “cosmetically and/or dermatologicallyacceptable carrier,” as used herein, means that the carrier is suitablefor topical application to the keratinous tissue, which includes safetyfor use in topical application and compatibility with the actives(fullerene-derived ketolactams) of the present invention.

A safe and effective amount of carrier is from about 50% to about99.999%, from about 60% to about 99.99%, from about 70% to about 99.9%,or from about 80% to about 99% of the composition, all said percentagesreferring to weight percent.

The active of the present invention may be either dissolved or suspendedas a solid particulate in the carrier. The active may be dissolved inone or more phases of the carrier, with only a small amount of theactive present as a suspended solid particulate. In certain embodiments,there is no measurable amount of active present as a suspended solidparticulate.

The carrier used in the present invention can be any of a wide varietyof forms, such as are commonly used in the art. Examples include but arenot limited to simple solutions (water or oil based), emulsions (creams,lotions) and solid forms (gels, sticks). Emulsion carriers, such ascommonly used in the art to make for example creams or lotions include,but are not limited to, oil-in-water, water-in-oil,water-in-oil-in-water, and oil-in-water-in-silicone emulsions.

In the case where the carrier is an emulsion and the active is dissolvedin the carrier, it is well known in the art that the active willdistribute in either the oil or water phase, depending on whether theactive is oil soluble or water soluble, or in the case where the activeis soluble in both oil and water (amphiphilic), or the active is presentas a suspended solid, the active may distribute in both the oil andwater phases, in a proportion depending on the relative solubilities ineach phase.

The actives as described herein may be used as a particulate componentof formulations which do or do not contain a liquid phase, such as solidor liquid makeup formulations.

A “polar compound” as used herein refers to hydrophilic or amphiphiliccompounds which dissolve in varying degrees in water. Polar compoundsmay be used to dissolve or solubilize an active of the instantinvention, or otherwise provide a hydrophilic or amphiphilc component ofthe carrier for an active of the present invention, with or without anoily phase present in the formulation, to form single phase ormulti-phase (emulsion) formulations, and with or without otheringredients in the formulation as described herein. Examples of suchpolar compounds are water, alcohols, mixtures of waters and alcohols,hydrogels consisting of water and alcohol components with a gellingagent, and other hydrophilic compounds as are typically used eitheralone or in combination with an oily phase to form single phaseformulations or bi-phasic emulsions. Examples of such bi-phasicformulations are lotions and creams. Other examples of polar compoundsare hydrophilic thickening agents, such as carbomers; solubilizingagents such as polymers, for example polyethylene glycol orpolyvinylpyrrolidone (PVP). Polar compounds as mentioned herein may beused in combination with hydrophilic or lipophilic versions of activeingredients described in the present invention.

One embodiment involves the use of an oil (lipid) soluble activedissolved in an oily carrier, wherein the oily carrier may be presentwith an aqueous phase to form an emulsion. In certain embodiments, theactive is dissolved in an oily carrier to form a simple solution.

An “oily carrier” as used herein refers to the compounds as are commonlyknown in the art to make cosmetics or dermatologic formulations, such asemulsions. Examples include naturally derived oils, waxes, or waxesters, synthetic oils, waxes, or wax esters. Silicones are alsoenvisioned as components of the carrier, as well as glycerine compounds,polymers, co-polymers, and other common formulation ingredients incosmetics.

Naturally derived oily carriers include but are not limited to apricotkernel oil, arachis oil, avocado oil, babassu oil, baobab oil,blackcurrant seed oil, borage oil, calendula oil, castor oil, coconutoil, cranberry seed oil, evening primrose oil, grape seed oil, hazelnutoil, hemp oil, illipe butter, jojoba oil, kukui nut oil, macadamia oil,mango butter, moring a oil, olive oil, papaya seed oil, peach kerneloil, plum oil, pomegranate seed oil, rapeseed oil, rice bran oil,rosehip oil, safflower oil, sesame oil, shea nut butter, soybean oil,strawberry seed oil, sunflower oil, sweet almond oil, and wheat germoil.

In certain embodiments, the active, which may be an underivatizedfullerene, a fullerene derivative, a fullerene-derived ketolactam isdissolved in a naturally-derived oily carrier. In certain embodiments,the carrier is grape seed oil, in a concentration between 0.001% (wt.)and 25% (wt.), between 0.01% (wt.) and 15% (wt.), or between 0.1% (wt.)and 5% (wt.). Other small amounts of compounds are normally present insuch naturally derived oily carriers, such as antioxidants (e.g.,polyphenolics), vitamins, fatty acids, esters, and the like and areacceptable for use in the carrier.

In certain embodiments, the active is present as a dissolved compound ina liquid oily carrier, in a concentration sufficient to impart enoughcolor to the carrier whereby the absorbance of the formulation comparedto the parent oil is increased in the range of 100% or more. This allowsfor less light to penetrate the solution, which serves to protect thesolution from potential photo-oxidation. In such embodiments, the colorimparted by the active is noticeably amber, brownish-red, brown, orgray. Underivatized fullerenes, if used to make such a formulation, maygive a magenta or reddish color. Different fullerenes, fullerenederivatives, or fullerene-derived keto-lactams may require differentconcentrations to give a similar optical density.

It has been found that such a simple solution of a fullerene, fullerenederivative, or fullerene-derived ketolactam dissolved in an oilysubstance provides for a particularly effective method of applying theactive to keratinous tissue, since it allows for a small amount offormulation to be applied for a given desired dosage of active, and withminimal other components which may alter or diminish the efficacy of theactive, or which may give unwanted side effects when applied to theskin. In addition, such simple solutions of a fullerene-derived orfullerene active wherein the optical density has been significantlyincreased compared to the parent carrier offer the advantage of beingmore stable with respect to UV or visible light induced oxidation.

Fullerenes, upon light absorbance, produce the triplet state withvarying yields depending on the fullerene and nature of chemicalderivative (from about 0.1-1 quantum yield, as described above), whichproduces singlet oxygen in varying yields depending on the fullerene andnature of chemical derivative (from about 0.1-1 quantum yield).Generation of singlet oxygen is known to produce degradation productsresulting from reaction of the singlet oxygen or other products of thefullerene triplet state (such as superoxide), for example epoxides, thathave been shown to be products of reaction of singlet oxygen with thetriplet excited state of the fullerene.

Reduction in the relative amount of degradation of any fullerene,fullerene derivative, or fullerene-derived ketolactam containing formulawould be desired, to minimize the loss of activity of the formula viaphotooxidation. Even for compounds, such as those of the presentinvention, which have a reduced net singlet oxygen generation, mayundergo photooxidation and break down, and thus it is desirable toreduce or prevent such photooxidation.

Reduction in the overall transmittance (making the formula moreoptically dense) is one way to accomplish a reduction in the overallpercentage of the active in a formulation that may photooxidize.

Light intensity in a liquid formulation, such as a liquid oilformulation, decays along the optical path according to the Beer-Lambertlaw:I₁/I_(o)=10^(−A)

Where I₁ is the intensity of light at a given location within thesample, I_(o) is the initial intensity of light, and A is theabsorbance. The intensity of light at a given location in theformulation correlates with the rate of photochemically activatedreaction, i.e., lower intensities correspond to lower rates ofphotochemical reaction, all other factors being equal.

Therefore increases in the absorbance (or decreases in thetransmittance) can have a dramatic effect on reducing the rate ofreaction of photooxidation. This effect is used practically, for exampleto reduce polymer photooxidation by addition of UV absorbers to decreasephoton density within a polymer.

In some cases, total photooxidation may not be prevented, but the amountof photooxidation may be reduced, allowing for example for a longershelf-life. Shelf-live of cosmetics products is important, since in theEU each product must display a “period after opening” (PAO) date, andlonger PAO dates are preferred.

Dyes or pigments (e.g., carbon black) may also be used to increase theabsorption and reduce photooxidation, as is known in the art to preventphotooxidation of polymers.

It is not common for cosmetics formulations to be strongly colored inappearance, as historically, it is believed that white or only slightlycolored cosmetics products are more desirable to the consumer. Thus, theminimization of photooxidation by increasing absorbance of theformulation and thus decreasing the incident light within theformulation has not been previously utilized.

It has been found that simple liquid lipid formulations wherein theformulation is visibly dark due to the presence of a fullerene,fullerene derivative, or fullerene-derived ketolactam remain stable forrelatively long times (e.g., 6, 9, or 12 months or more), and thiseffect is believed to be at least partly due to the effect of theformulation being significantly more optically dense than the neatparent oil. For example, it is known in the art that a dilute solutionof C₆₀ in toluene exposed to light and air will undergo approximately10% or more degradation and loss of the C₆₀ due to epoxidation andsubsequent breakdown of the fullerene cage resulting from singlet oxygengenerated via photoexcitation of the C₆₀. This can be seen even visuallysince the decomposed C₆₀ forms a blackish product which settles out ofsolution.

Formulations of a fullerene derivative and HG2-V1 and HG2-V2 dissolvedin grape seed oil which are noticeably darker than the parent oil, butwhich still are convenient for use on the skin (e.g., no staining of theskin is observed and the formulation is not unpleasant to use) exposedto light and air for up to a year give a reduced amount of decompositionproducts.

Likewise, it has been discovered that fullerenes or fullerenederivatives dissolved in a suitable solvent (e.g. aromatic) atsufficiently high concentrations to reduce the optical transmittance ofthe solution react with a slower rate, as a percentage of the startingfullerene or fullerene derivative concentration, when exposed to lightcompared to similar solutions at a lower concentration.

The formulation is therefore envisioned in which any fullerene,fullerene derivative, or fullerene-derived ketolactam is dissolved in anoily carrier oil in the range of about 0.001% (wt.) to 20% (wt.), 0.01%(wt.) to 10% (wt.), or 0.1% (wt.) to 5% (wt.), wherein the formulationis significantly more optically dense than the parent carrier. Theincrease of the optical density of the formulation may be accomplishedby the active itself, but may optionally be accomplished by the additionof dyes, pigments, or other coloring agents. It is described below howone may determine such an optimal concentration of the dyeing agent; incertain embodiments, the dyeing agent is also the active ingredient (thefullerene, fullerene derivative or fullerene-derived ketolactam), tominimize, reduce, or eliminate the photochemically activateddecomposition of the formulation.

Naturally-derived oily carriers, such as grapeseed oil, olive oil,jojoba oil (technically a wax ester), or sunflower oil, which arecommonly used in cosmetics formulations have a low absorbance of lightat a wavelength (λ) of approximately λ=570 nm. Consequently, these oilsare pale yellow, green, or yellow-green. Examples of the UV-Vis spectra(measured against water) of various commercially available oils (anolive oil, a jojoba oil, and a grapeseed oil) are shown in FIG. 5.

All of these oils show an absorbance (A) at λ=570 nm of A₅₇₀ less than0.05 when measuring the neat oil against water, using 1 cm cuvettes asis general practice. The above absorbance profiles were measured byplacing the neat oil in the 1 cm path length spectrometer cuvette. Itcan be seen that the oils do not absorb significantly in the visible orUV visible regions, and visually, they are relatively clear, onlylightly colored solutions of a yellowish, or greenish yellow color.Olive oil typically has a darker appearance (and is thus more opticallydense) than the other oils, and this can be seen in the absorptionprofile.

Spectra of various fullerene derivatives and a fullerene-derivedketolactam of the instant invention dissolved in neat grapeseed oil aredepicted in FIG. 6. It is clear that invariably there is a moresignificant absorbance at 570 nm, even though the neat oil shows almostno absorbance at this wavelength as was shown above. The fullerenederivatives and fullerene-derived ketolactam also noticeably increasethe absorption profile compared to the neat parent oil throughout therange of UV and visible wavelengths. 570 nm is chosen as a convenientwavelength at which to measure the increase of optical absorption, or“darkness” or “optical opacity” of the finished formulation.

Un-derivatized fullerenes also may impart the desired increase inabsorbance and thus allow for less photooxidation and improvedshelf-life. Figure below shows underivatized fullerenes (a mixture ofC₆₀/C₇₀/higher fullerenes approximately in the molar proportion70%/25%/5%). It can be seen that the formulation has a significantlyincreased optical absorption compared to the neat parent grapeseed oilas shown FIG. 7. Visually, the formulation is noticeably darker and moreoptically opaque than the parent neat grapeseed oil.

Fullerenes higher in molecular weight than C₆₀, the “higher fullerenes,”e.g., C₇₀, C₇₆, C₇₈, C₈₄, typically have significantly higher opticalabsorption values than C₆₀, and so it may be desirable in some cases touse C₇₀, C₇₆, C₇₈, or C₈₄, either alone or in mixtures, or chemicalderivatives of the higher fullerenes either alone or in mixtures toincrease the optical density of a formulation. Depending on whichfullerene is used or if a chemical derivative is used, the relativeincrease in absorption compared to the neat parent oil may differ.Certain fullerenes may offer a different absorption value at the sameconcentration.

In many instances, the concentration of fullerene, fullerene derivative,or fullerene-derived ketolactam desired due to considerations of optimalantioxidant efficacy is higher than can be conveniently measured bystandard UV/vis spectroscopy. For concentrated solutions, dilution maybe necessary to obtain a proper spectrum in the so-called visible area(λ=400-700 nm). If such concentrated solutions are measured withoutdilution, A₅₇₀ may exceed a limit to obtain an accurate measurement, ormay even exceed the maximum value that can be measured by thespectrometer. As an example, the spectrum of a concentrated solution ofHG2-V2 in grapeseed oil (9.2 mg HG2-V2 dissolved in 3 mL), diluted ×10(v/v) with toluene, is shown in FIG. 8. Here, A₅₇₀ is 0.24, meaning thatwithout dilution it would give approximately A=2.4. Common UV-Visspectrometers can usually measure up to A≈5, meaning that for thissolution a large part of the spectrum (λ<510 nm) could not have beenaccurately measured without dilution.

Such increases in optical absorbance may also be utilized forcosmetically or dermatologically acceptable formulations which aremulti-phase, such as emulsions, as described herein, by increasing theabsorbance, as described herein, of the liquid component in which thefullerene, fullerene derivative, or fullerene-derived ketolactam isdissolved or suspended, for example by measurement of the absorbance ofsaid liquid phase before addition of other liquid phases, emulsifiers,etc., for example when forming a cream or lotion.

It is taught herein that a simple formulation wherein a fullerene,fullerene derivative, or fullerene-derived ketolactam is dissolved in aliquid lipid oil gives desirable properties of formulation of a radicalscavenger for skin care application, allowing for a minimal number ofingredients that may diminish the efficacy.

It is also taught herein that addition of an epoxidized version of afullerene, fullerene derivative, or fullerene-derived ketolactam to aformulation intended for skin care application can act to preserve theformulation and/or reduce the generation of singlet oxygen and/orsuperoxide formed by photoexcited states of said fullerene, fullerenederivative, or fullerene derived ketolactam. This follows from thefinding (see Example 3[f]) that though the quantum yield of ¹O₂generation of fullerenes and fullerene derivatives is high (up to 1.0),the net generation of ¹O₂ is surprisingly low compared to well-knownphotosensitizers, such as methylene blue (MB), and lower than would bepredicted by the singlet oxygen quantum yield and optical absorption ofthe fullerene, fullerene derivative, or fullerene-derived ketolactam.The ¹O₂ quantum yield of MB is ˜0.5, about half of PCBM (˜1.0), however,the net generation of ¹O₂ is 250 times higher for MB than for PCBM on anequimolar basis. The average optical absorption between 400 nm and 700nm is about 10 times higher for MB compared to PCBM, therefore, MBproduces 25 times the amount of ¹O₂ as PCBM on an equal absorption andequimolar basis, though it has a ¹O₂ quantum yield half that of PCBM.This demonstrates the effect that the net ¹O₂ generation of fullerenesis in fact much lower than expected, due to the quenching effects ofepoxide reaction products formed by the photooxidation, which are knownto be quenchers of the photoexcited fullerene triplet state. However,the effect of fullerene epoxides on the net generation of ¹O₂ has notbeen demonstrated until now. Therefore, addition of mono- andmulti-epoxidized fullerenes, fullerene derivatives, or fullerene-derivedketolactams to a formulation can act to minimize the reaction productsof the photoexcited states of the fullerene, fullerene derivative, orfullerene-derived ketolactam.

It is further taught herein that one skilled in the art may prolongshelf-life of the formulation by taking into account what minimumconcentrations are necessary to impart increased absorbance to theformulation, as measured by the optical absorption spectra at wavelengthof 570 nm, so as to reduce photooxidation and increase the shelf-life ofthe formulation. Therefore, it is taught herein that in cases where theactive concentration is thought to be sufficient in terms of antioxidantefficacy, it may be advantageous to increase the concentration of activeor add a light absorbing additive to increase the optical absorption andthus decrease the potential for photochemically activated oxidation ofthe formulation, and thus to provide a more stable formulation from thestandpoint of shelf-life. Having such optically dense formulationsallows for more packaging options, e.g., glass containers which are notamber colored, to be used, which may be desired in some cases so as tocreate a more appealing product. Optically dense formulations of thepresent invention utilizing fullerenes, fullerene derivatives, orfullerene-derived ketolactams are also surprisingly not unpleasant inuse, since the darkness of the formulations does not stain the skin fora significant period of time. Further, having a more optically denseformulation may also confer advantages after application, as the filmformed on the skin is resultantly also more optically dense, and thusallows for less light transmittance through the film to the portions ofactive which penetrate the skin.

A formulation wherein the photooxidation properties are improved may beobtained by measuring the increase in optical absorption at 570 nm asmeasured by placing the liquid oil formulation in a 1 cm cuvette andensuring A₅₇₀ is 0.1 or greater, which for most oils amounts to anincrease in the optical density by a factor of 2 or more compared to theneat parent oil. In certain embodiments, A₅₇₀ of the final formulationof fullerene, fullerene derivative or fullerene-derived ketolactamdissolved or suspended in an oily carrier is 0.25 or higher. In otherembodiments, A₅₇₀ of the final formulation is greater than 0.5. Forreference, for an oil such as grape seed oil where the absorbance at 570nm is approximately 0.01, an increase of the absorbance to 0.1 can becalculated by Beer-Lambert's law to amount to approximately a 20%decrease in transmitted light intensity at 570 nm, and assuming firstorder kinetics of photoactivation, roughly a 20% decrease in the rate ofphotochemical oxidation, as the increase in absorbance is typicallythroughout the visible and UV spectrum. Similarly, an increase toabsorbance of 0.5 decreases the rate of photochemical oxidationapproximately 70%.

Other optional compounds which may be added to this formulation includeperfume agents, such as but not limited to essential oils or syntheticadditives as commonly used in the perfume industry, in the range ofbetween 0.00001% (wt.) and 1% (wt.), or in the range of 0.0001% (wt.) to0.001% (wt.). Such perfume agents include those as are commonly used inthe art to make perfumes, such as lavender oil, and other oils derivedfrom plant or animal sources. One such formulation includes the use ofpure lavender oil obtained naturally (Product #301981, “Pure LavenderOil” from Norfolk Lavender, Ltd., UK) in a concentration ofapproximately 0.0003% (wt.) added to the grapeseed oil carrier, whichcontains HG2-V2 for example in a concentration in the range about 0.1%(wt.) to about 0.6% (wt.). This concentration of the lavender oilimparts a barely perceptible note of lavender, and serves to mask thefaint odor of the grape seed oil, without giving a noticeably strongscent. Lavender oil is one scent that may be used in the invention as ithas been shown to have beneficial aromatherapeutic properties, is welltolerated by the skin, and has been shown as well to have beneficialproperties in skincare, such as anti-inflammatory properties.

In addition, other lipid soluble compounds, including but not limited toantioxidants, including but not limited to Vitamin E, retinoids,polyphenolic compounds, Coenzyme Q10, or other active additives may beadded to the formulation. In some cases, additives necessary for thestability and preservation of the carrier may be necessary, as describedunder the heading “Other Components” in the present document.

Such a formulation as described above has the advantages of providing asafe and effective amount of the active while being made of fewcomponents and with minimal use of other carrier compounds which arenecessary for more complex formulations, such as emulsions. For example,anti-microbial agents are typically not necessary if an aqueous phase isnot present. Likewise, emulsifiers are not necessary if the formulationis single phase. In addition the presence of a bi-phase emulsion or thepresence of other compounds may alter the transport and/or affinity ofthe fullerene-derived ketolactams of the present invention, and so it isdesirable to preserve the inherent solubility and affinity of thecompounds of the present invention without any alteration in theseproperties that may be caused by the presence of other compounds. Thus,this skincare formulation provides for topical application of only thefree radical scavengers of the present invention with the need for lessother compounds which may not provide benefits or may even provideunwanted side effects. Such a formulation provides efficient delivery ofthe compounds of the present invention past the stratum corneum barrier,which is mainly lipophilic.

Alternatively, water soluble versions of the active may be used to formoptically dense simple solutions as described above, where the carrieris aqueous or polar, such as water or alcohols, and the active ispresent as a suspended particulate, or dissolved in the aqueous carrier.

Other suitable carriers comprise an emulsion such as oil-in-wateremulsions (e.g., silicone in water) and water-in-oil emulsions, (e.g.,water-in-silicone emulsions). As will be understood by the skilledartisan, a given component will distribute primarily into either thewater or oil phase, depending on the water solubility/dispensability ofthe component in the composition.

Emulsions according to the present invention generally contain anaqueous phase and a lipid or oil. Emulsions may further contain fromabout 0.1% (wt.) to about 10% (wt.), or from about 0.2% (wt.) to about5% (wt.), of an emulsifier, based on the weight of the composition.Emulsifiers may be nonionic, anionic or cationic. Suitable emulsifiersare disclosed in, for example, McCutcheon's Detergents and Emulsifiers,North American Edition, pages 317-324 (1986). Suitable emulsions mayhave a wide range of viscosities, depending on the desired product form,to form what is known in the art as lotions or creams.

The acceptable carriers of the present invention may also contain avariety of other ingredients that are conventionally used in givenproduct types provided that they do not unacceptably alter the benefitsof the invention.

The optional components, when incorporated into the composition, shouldbe suitable for use in contact with human keratinous tissue withoutundue toxicity, incompatibility, instability, allergic response, and thelike within the scope of sound judgment. The CTFA Cosmetic IngredientHandbook, Second Edition (1992) describes a wide variety of nonlimitingcosmetic and pharmaceutical ingredients commonly used in the skin careindustry, which are suitable for use in the compositions of the presentinvention. Examples of these ingredient classes include: abrasives,absorbents, aesthetic components, such as fragrances, pigments,colorings/colorants, essential oils, skin sensates, astringents, etc.(e.g., clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyllactate, witch hazel distillate), anti-acne agents, anti-caking agents,antifoaming agents, antimicrobial agents (e.g., iodopropylbutylcarbamate), antioxidants, binders, biological additives, bufferingagents, bulking agents, chelating agents, chemical additives, colorants,cosmetic astringents, cosmetic biocides, denaturants, drug astringents,external analgesics, film formers or materials, e.g., polymers, foraiding the film-forming properties and substantivity of the composition(e.g., copolymer of eicosene and vinyl pyrrolidone), opacifying agents,pH adjusters, propellants, reducing agents, sequestrants, skin bleachingand lightening agents, skin-conditioning agents, skin soothing and/orhealing agents and derivatives, skin treating agents, thickeners, andvitamins and derivatives thereof.

Formulations containing the compounds of the present invention intendedfor topical use in skincare may contain from 0.001% (wt.) or less to upto 20% (wt.) or more of the compound(s) of the present invention,depending on the intended use and/or specific compound.

Oxidative stress caused by free radicals from environmental sources,such as exposure to light, pollution, cigarette smoke, atmosphericozone, etc. may be prevented or remediated through the use of thepresent compounds.

The compounds of the present invention may be used as agents toameliorate immune system responses to various conditions involve thegeneration of free radical species, such as .NO, which is generated bythe immune system to combat bacterial infection, in response toirritants, etc. For example, the red, swollen appearance of acne lesionsmay be reduced through the application of the present compounds.

Likewise, the inflammatory responses coincident with psoriasis, eczema,rosacea and other conditions that are the result of immune systemresponse may be reduced.

The compounds of the present invention are also envisioned to improvethe overall health and appearance of the skin, especially of the face.Improvements in overall health may be gained through reduction inwrinkles, regulation of dryness and oiliness, improvement in skinthickness, reduction of hyper-pigmentation (age spots, moles, or otherdiscoloration), reduction of scarring caused by skin wounds, acnelesions, or other conditions leading to scarring, and other improvementsin the overall healthiness of the skin.

The compounds of the present invention may be used for minimizing theeffects of exposure to the sun, e.g., application after sun exposure tominimize sun-burn and peeling. The compounds of the present inventionmay also be used to prevent oxidative damage caused by exposure tosunlight.

The compounds of the present invention may be used where no pre-existingcondition exists, to provide moisturizing benefits and/or for theprevention of free radical-related conditions, such as acne,photo-aging, etc.

The compounds of the present invention may be used to ameliorate theeffects of “chemical peel” treatments, such as commonly performed usingα-glycolic acids, β-glycolic acids, lactic acids, or other chemicalagents, allowing for accelerated re-appearance of healthy skin,reduction in sensitivity, or other effects of chemical peel treatments.

The compounds of the present invention may be used to ameliorate theeffects of laser treatments of the skin, such as commonly performed forreduction in wrinkles, removal of tattoos, removal of abnormal growths,removal of hyper-pigmentation or other uses, allowing for acceleratedre-appearance of healthy skin, reduction in sensitivity, or othereffects of laser treatments.

The compounds of the present invention may be used to accelerate healingof wounds to the skin.

The compounds of the present invention may be used to prevent,ameliorate, or remediate abnormal skin growths, such as non-cancerous orcancerous growths, such as melanoma, warts, or cysts.

In general, any condition where free radicals lead to damage or otherdetriment to the skin may be ameliorated through use of the presentcompounds, such as erythema caused by radiation treatment orchemotherapy, sun-burn and peeling, chemical or thermal burns,inflammatory disorders, photo-aging, wrinkling, loss of skin thickness,extrinsic aging leading to sagging of the skin, sallow color, etc.

The present compounds are also envisioned to accelerate the naturalhealing of such conditions, such as but not limited to: damage to theskin caused by inflammatory responses, such as acne, psoriasis, eczema,skin wounds, laser treatment, chemical peels, radiation treatment,chemotherapy, thermal burns, or other unhealthy conditions of the skin.

The present compounds are envisioned to be used as a component in oradditive to sun screen or sun-block formulations to prevent orameliorate the effects of sun exposure, such as erythema.

The compounds of the present invention may also be used either alone orin conjunction with other nutritional or pharmaceutical ingredients informulations which are well known in the art, such as drug-deliveryagents, excipient agents, etc. for oral, intravenous, sub-lingual,intra-muscular or other dosing methods in humans or animals for theprevention or amelioration of conditions, such as deterioratingneurological conditions, such as Parkinson's disease, Alzheimer'sdisease, or other neurological conditions where ROS are implicated ascausative or exacerbating agents. In addition, the compounds of thepresent invention may be used to ameliorate or prevent atherosclerosis,increase general health, increase life-span, or for other conditionswhere antioxidants are used or prescribed.

The compounds of the present invention may be used as radical scavengingagents in non-biological applications where radical scavenging isdesired, such as food preservatives, polymer preservatives, personalcare formulation preservatives, or other applications where antioxidantsare commonly used.

In addition, the fullerene-derived ketolactam derivatives exhibit lowerLUMO levels than the parent fullerene, which may be desirable in variousorganic electronics applications for us as an n-type or ambipolarsemiconductor. Organic electronics applications include but are notlimited to organic photodiodes (photovoltaics, photodetectors), ororganic transistors. The lower LUMO levels of the fullerene-derivedketolactam compared to the parent fullerene may be particularlyapplicable for use as an n-type or ambipolar semiconductor in organictransistor applications.

Definitions

For convenience, certain terms employed in the specification, examples,and appended claims are collected here.

The term “adduct” is art-recognized and refers to a new molecularspecies (AB) formed by direct combination of two separate molecularentities (A+B). The term “bis-adduct” refers to molecular species AB₂.The term “tris-adduct” refers to molecular species AB₃. The terms“adduct” and “derivative” are used interchangeably herein. In certainembodiments, species A represents the fullerene core and species B anaddend.

The term “addend” refers to a chemical which is bonded to the fullerenecore. For example, the phenyl-pentanoic-acid-methyl-ester moiety of PCBMis referred to as an addend moiety.

The term “fullerene-derived ketolactam” refers to a chemical with thestructure of Molecule 1 (FIG. 1), where R can be any chemical group.Said fullerene-derived ketolactams may be further altered by themodification of the fullerene cage to include one or more additionalketolactam moieties, and/or the addition of one or more chemicaladdends, as described above.

The term “animal” as used herein may mean fish, amphibians, reptiles,birds, and mammals, such as mice, rats, rabbits, goats, cats, dogs,cows, and apes.

The term “heteroatom” is art-recognized and refers to an atom of anyelement other than carbon or hydrogen. Illustrative heteroatoms includeboron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term “alkyl” is art-recognized, and includes saturated aliphaticgroups, including straight-chain alkyl groups, branched-chain alkylgroups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl groups. In certain embodiments,a straight chain or branched chain alkyl has about 30 or fewer carbonatoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ forbranched chain), and alternatively, about 20 or fewer. Likewise,cycloalkyls have from about 3 to about 10 carbon atoms in their ringstructure, and alternatively about 5, 6 or 7 carbons in the ringstructure.

Unless the number of carbons is otherwise specified, “lower alkyl”refers to an alkyl group, as defined above, but having from one to aboutten carbons, alternatively from one to about six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths.

The term “aralkyl” is art-recognized and refers to an alkyl groupsubstituted with an aryl group (e.g., an aromatic or heteroaromaticgroup).

The terms “alkenyl” and “alkynyl” are art-recognized and refer tounsaturated aliphatic groups analogous in length and possiblesubstitution to the alkyls described above, but that contain at leastone double or triple bond respectively.

The term “aryl” is art-recognized and refers to 5-, 6- and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, naphthalene, anthracene, pyrene,pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole,pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.Those aryl groups having heteroatoms in the ring structure may also bereferred to as “aryl heterocycles” or “heteroaromatics.” The aromaticring may be substituted at one or more ring positions with suchsubstituents as described above, for example, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,heterocyclyl, aromatic or heteroaromatic moieties, —CF₃, —CN, or thelike. The term “aryl” also includes polycyclic ring systems having twoor more cyclic rings in which two or more carbons are common to twoadjoining rings (the rings are “fused rings”) wherein at least one ofthe rings is aromatic, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl”, “heteroaryl”, or “heterocyclic group” areart-recognized and refer to 3- to about 10-membered ring structures,alternatively 3- to about 7-membered rings, whose ring structuresinclude one to four heteroatoms. Heterocycles may also be polycycles.Heterocyclyl groups include, for example, thiophene, thianthrene, furan,pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole,imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,thiolane, oxazole, piperidine, piperazine, morpholine, lactones,lactams, such as azetidinones and pyrrolidinones, sultams, sultones, andthe like. The heterocyclic ring may be substituted at one or morepositions with such substituents as described above, as for example,halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino,nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl,carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, aheterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or thelike.

The terms “polycyclyl” or “polycyclic group” are art-recognized andrefer to two or more rings (e.g., cycloalkyls, cycloalkenyls,cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbonsare common to two adjoining rings, e.g., the rings are “fused rings”.Rings that are joined through non-adjacent atoms are termed “bridged”rings. Each of the rings of the polycycle may be substituted with suchsubstituents as described above, as for example, halogen, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, aheterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or thelike.

The term “carbocycle” is art-recognized and refers to an aromatic ornon-aromatic ring in which each atom of the ring is carbon.

The term “nitro” is art-recognized and refers to —NO₂; the term“halogen” is art-recognized and refers to —F, —Cl, —Br or —I; the term“sulfhydryl” is art-recognized and refers to —SH; the term “hydroxyl”means —OH; and the term “sulfonyl” is art-recognized and refers to —SO₂⁻. “Halide” designates the corresponding anion of the halogens, and“pseudohalide” has the definition set forth on 560 of “AdvancedInorganic Chemistry” by Cotton and Wilkinson.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R50, R51 and R52 each independently represent a hydrogen, analkyl, an alkenyl, —(CH₂)_(m)—R61, or R50 and R51, taken together withthe N atom to which they are attached complete a heterocycle having from4 to 8 atoms in the ring structure; R61 represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zeroor an integer in the range of 1 to 8. In certain embodiments, only oneof R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogentogether do not form an imide. In other embodiments, R50 and R51 (andoptionally R52) each independently represent a hydrogen, an alkyl, analkenyl, or —(CH₂)_(m)—R61. Thus, the term “alkylamine” includes anamine group, as defined above, having a substituted or unsubstitutedalkyl attached thereto, i.e., at least one of R50 and R51 is an alkylgroup.

The term “acylamino” is art-recognized and refers to a moiety that maybe represented by the general formula:

wherein R50 is as defined above, and R54 represents a hydrogen, analkyl, an alkenyl or —(CH₂)_(m)—R61, where m and R61 are as definedabove.

The term “amido” is art recognized as an amino-substituted carbonyl andincludes a moiety that may be represented by the general formula:

wherein R50 and R51 are as defined above. Certain embodiments of theamide in the present invention will not include imides which may beunstable.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. In certain embodiments, the“alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl,—S-alkynyl, and —S—(CH₂)_(m)—R61, wherein m and R61 are defined above.Representative alkylthio groups include methylthio, ethyl thio, and thelike.

The term “carboxyl” is art recognized and includes such moieties as maybe represented by the general formulas:

wherein X50 is a bond or represents an oxygen or a sulfur, and R55 andR56 represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R61 or apharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl,an alkenyl or —(CH₂)_(m)—R61, where m and R61 are defined above. WhereX50 is an oxygen and R55 or R56 is not hydrogen, the formula representsan “ester”. Where X50 is an oxygen, and R55 is as defined above, themoiety is referred to herein as a carboxyl group, and particularly whenR55 is a hydrogen, the formula represents a “carboxylic acid”. Where X50is an oxygen, and R56 is hydrogen, the formula represents a “formate”.In general, where the oxygen atom of the above formula is replaced bysulfur, the formula represents a “thiolcarbonyl” group. Where X50 is asulfur and R55 or R56 is not hydrogen, the formula represents a“thiolester.” Where X50 is a sulfur and R55 is hydrogen, the formularepresents a “thiolcarboxylic acid.” Where X50 is a sulfur and R56 ishydrogen, the formula represents a “thiolformate.” On the other hand,where X50 is a bond, and R55 is not hydrogen, the above formularepresents a “ketone” group. Where X50 is a bond, and R55 is hydrogen,the above formula represents an “aldehyde” group.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,—O—(CH₂)_(m)—R61, where m and R61 are described above.

The term “sulfonate” is art recognized and refers to a moiety that maybe represented by the general formula:

in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term “sulfate” is art recognized and includes a moiety that may berepresented by the general formula:

in which R57 is as defined above.

The term “sulfonamido” is art recognized and includes a moiety that maybe represented by the general formula:

in which R50 and R56 are as defined above.

The term “sulfamoyl” is art-recognized and refers to a moiety that maybe represented by the general formula:

in which R50 and R51 are as defined above.

The term “sulfonyl” is art-recognized and refers to a moiety that may berepresented by the general formula:

in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term “sulfoxido” is art-recognized and refers to a moiety that maybe represented by the general formula:

in which R58 is defined above.

The term “phosphoryl” is art-recognized and may in general berepresented by the formula:

wherein Q50 represents S or O, and R59 represents hydrogen, a loweralkyl or an aryl. When used to substitute, e.g., an alkyl, thephosphoryl group of the phosphorylalkyl may be represented by thegeneral formulas:

wherein Q50 and R59, each independently, are defined above, and Q51represents O, S or N. When Q50 is S, the phosphoryl moiety is a“phosphorothioate”.

The term “phosphoramidite” is art-recognized and may be represented inthe general formulas:

wherein Q51, R50, R51 and R59 are as defined above.

The term “phosphonamidite” is art-recognized and may be represented inthe general formulas:

wherein Q51, R50, R51 and R59 are as defined above, and R60 represents alower alkyl or an aryl.

Analogous substitutions may be made to alkenyl and alkynyl groups toproduce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls,amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls.

The definition of each expression, e.g., alkyl, m, n, and the like, whenit occurs more than once in any structure, is intended to be independentof its definition elsewhere in the same structure.

The term “selenoalkyl” is art-recognized and refers to an alkyl grouphaving a substituted seleno group attached thereto. Exemplary“selenoethers” which may be substituted on the alkyl are selected fromone of —Se-alkyl, —Se-alkenyl, —Se-alkynyl, and —Se—(CH₂)_(m)—R61, m andR61 being defined above.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations.

Certain compounds contained in compositions of the present invention mayexist in particular geometric or stereoisomeric forms. In addition,polymers of the present invention may also be optically active. Thepresent invention contemplates all such compounds, including cis- andtrans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers,(L)-isomers, the racemic mixtures thereof, and other mixtures thereof,as falling within the scope of the invention. Additional asymmetriccarbon atoms may be present in a substituent such as an alkyl group. Allsuch isomers, as well as mixtures thereof, are intended to be includedin this invention.

If, for instance, a particular enantiomer of compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction.

The term “substituted” is also contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissiblesubstituents include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic substituents oforganic compounds. Illustrative substituents include, for example, thosedescribed herein above. The permissible substituents may be one or moreand the same or different for appropriate organic compounds. Forpurposes of this invention, the heteroatoms, such as nitrogen may havehydrogen substituents and/or any permissible substituents of organiccompounds described herein which satisfy the valences of theheteroatoms. This invention is not intended to be limited in any mannerby the permissible substituents of organic compounds.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991). Protected forms of the inventive compounds are included withinthe scope of this invention.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

Certain Compositions and Uses of the Invention

Formula I

One aspect of the present invention relates to a fullerene-derivedketolactam selected from the group consisting of C₆₀-derived ketolactamcompounds of formula I:

or compounds of formula I wherein one or more additional addends arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof, wherein R is a C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl, orC₁-C₃₀ alkynyl, said alkyl, alkenyl or alkynyl being optionallysubstituted with a C₁-C₂₀ alkyl group, aryl group, heteroaryl group,halogen atom, or hydroxyl group, said aryl or heteroaryl beingoptionally substituted with a halogen atom, hydroxyl group, C₁-C₃₀ alkylgroup, C₁-C₃₀ linear alkoxy group, or a —O(CH₂CH₂O)_(n)R′ group; n is 1to 100 inclusive, and R′ is hydrogen, aryl, C₁-C₃₀ alkyl, C₁-C₃₀ alkenylor C₁-C₃₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀ branchedalkoxy group.

Another aspect of the present invention relates to a fullerene-derivedketolactam selected from the group consisting of C₆₀-derived ketolactamcompounds of formula I:

or compounds of formula I wherein one or more additional addends arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof, wherein R is a C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl, orC₁-C₃₀ alkynyl, said alkyl, alkenyl or alkynyl being optionallysubstituted with a C₁-C₂₀ alkyl group, aryl group, heteroaryl group,halogen atom, or hydroxyl group, said aryl or heteroaryl beingoptionally substituted with two or more groups independently selectedfrom the group consisting of halogen atoms, hydroxyl groups, C₁-C₃₀alkyl groups, C₁-C₃₀ alkoxy groups, and O(CH₂CH₂O)_(n)R′ groups; n is 1to 100 inclusive, and R′ is hydrogen, aryl, C₁-C₃₀ alkyl, C₁-C₃₀ alkenylor C₁-C₃₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀ branchedalkoxy group.

Another aspect of the present invention relates to a fullerene-derivedketolactam selected from the group consisting of C₆₀-derived ketolactamcompounds of formula I:

or compounds of formula I wherein one or more additional addends arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof, wherein R is a C₁-C₃₀ alkyl, alkenyl, oralkynyl, said alkyl, alkenyl or alkynyl being optionally substitutedwith two or more groups independently selected from the group consistingof C₁-C₂₀ alkyl groups, aryls, heteroaryls, halogens, and hydroxylgroups, said aryl or heteroaryl being optionally substituted with one ormore groups independently selected from the group consisting of halogenatoms, hydroxyl groups, C₁-C₃₀ alkyl groups, C₁-C₃₀ alkoxy groups, andO(CH₂CH₂O)_(n)R′ groups; n is 1 to 100 inclusive; and R′ is hydrogen,aryl, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl or C₁-C₃₀ alkynyl. In certainembodiments, R may be a C₉-C₅₀ branched alkoxy group.

Another aspect of the present invention relates to a fullerene-derivedketolactam selected from the group consisting of C₆₀-derived ketolactamcompounds of formula I:

or compounds of formula I wherein one or more additional addends arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof, wherein R is aryl or heteroaryl, said aryl orheteroaryl being optionally substituted with one or more groupsindependently selected from the group consisting of halogen atoms,hydroxyl groups, C₁-C₃₀ alkyl groups, C₁-C₃₀ alkoxy groups, andO(CH₂CH₂O)_(n)R′ groups; n is 1 to 100 inclusive; and R′ is hydrogen,aryl, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl, or C₁-C₃₀ alkynyl. In certainembodiments, R may be a C₉-C₅₀ branched alkoxy group.

In certain embodiments, R is a C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl, or C₁-C₅₀alkynyl, said alkyl, alkenyl or alkynyl being optionally substitutedwith a C₁-C₅₀ alkyl group, aryl group, heteroaryl group, halogen atom,or hydroxyl group, said aryl or heteroaryl being optionally substitutedwith a halogen atom, hydroxy group, C₁-C₅₀ alkyl group, C₁-C₅₀ linearalkoxy group, or a ˜O(CH₂CH₂O)_(n)R′ group; n is 1 to 100 inclusive; andR′ is hydrogen, aryl, C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl or C₁-C₅₀ alkynyl. Incertain embodiments, R may be a C₉-C₅₀ branched alkoxy group.

In certain other embodiments, R is a C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl, orC₁-C₅₀ alkynyl, said alkyl, alkenyl or alkynyl being optionallysubstituted with a C₁-C₅₀ alkyl group, aryl group, heteroaryl group,halogen atom, or hydroxyl group, said aryl or heteroaryl beingoptionally substituted with two or more groups independently selectedfrom the group consisting of halogen atoms, hydroxy groups, C₁-C₅₀ alkylgroups, C₁-C₅₀ alkoxy groups, and O(CH₂CH₂O)_(n)R′ groups; n is 1 to 100inclusive; and R′ is hydrogen, aryl, C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl orC₁-C₅₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀ branchedalkoxy group.

In still other embodiments, R is a C₁-C₅₀ alkyl, alkenyl, or alkynyl,said alkyl, alkenyl or alkynyl being optionally substituted with two ormore groups independently selected from the group consisting of C₁-C₅₀alkyl groups, aryls, heteroaryls, halogens, and hydroxyl groups, saidaryl or heteroaryl being optionally substituted with one or more groupsindependently selected from the group consisting of halogen atoms,hydroxy groups, C₁-C₅₀ alkyl groups, C₁-C₅₀ alkoxy groups, andO(CH₂CH₂O)_(n)R′ groups; n is 1 to 100 inclusive; and R′ is hydrogen,aryl, C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl or C₁-C₅₀ alkynyl. In certainembodiments, R may be a C₉-C₅₀ branched alkoxy group.

In yet other embodiments, R is aryl or heteroaryl, said aryl orheteroaryl being optionally substituted with one or more groupsindependently selected from the group consisting of halogen atoms,hydroxy groups, C₁-C₅₀ alkyl groups, C₁-C₅₀ alkoxy groups, andO(CH₂CH₂O)_(n)R′ groups; n is 1 to 100 inclusive; and R′ is hydrogen,aryl, C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl, or C₁-C₅₀ alkynyl. In certainembodiments, R may be a C₉-C₅₀ branched alkoxy group.

Formula II

One aspect of the present invention relates to a fullerene-derivedketolactam selected from the group consisting of C₆₀-derived ketolactamcompounds of formula II:

or compounds of formula II wherein one or more additional addends arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof, wherein n is 2 to 30 inclusive; R is selectedfrom the group consisting of H, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl, C₁-C₃₀alkynyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, aryl orheteroaryl being optionally substituted with one or more groupsindependently selected from the group consisting of halogen atoms,hydroxyl groups, C₁-C₃₀ alkyl groups, C₁-C₃₀ alkoxy groups, andO(CH₂CH₂O)_(n)R′ groups; n is 1 to 100 inclusive; and R′ is H or aryl orC₁-C₃₀ alkyl, C₁-C₃₀ alkenyl or C₁-C₃₀ alkynyl. In certain embodiments,R may be a C₉-C₅₀ branched alkoxy group.

In certain embodiments, n is 2 to 30 inclusive; R is selected from thegroup consisting of H, C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl, C₁-C₅₀ alkynyl,aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, aryl or heteroarylbeing optionally substituted with one or more groups independentlyselected from the group consisting of halogen atoms, hydroxy groups,C₁-C₅₀ alkyl groups, C₁-C₅₀ alkoxy groups, and O(CH₂CH₂O)_(n)R′ groups;n is 1 to 100 inclusive; and R′ is H or aryl or C₁-C₅₀ alkyl, C₁-C₅₀alkenyl or C₁-C₅₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀branched alkoxy group.

Formula III

Another aspect of the present invention relates to a fullerene-derivedketolactam selected from the group consisting of C₆₀-derived ketolactamcompounds of formula III:

or compounds of formula III wherein one or more additional addends arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof, wherein X is selected from the group consistingof H, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl, C₁-C₃₀ alkynyl, aryl, andheteroaryl, said alkyl, alkenyl, alkynyl, aryl, or heteroaryl beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxyl groups, C₁-C₃₀alkyl groups, C₁-C₃₀ alkoxy groups, and O(CH₂CH₂O)_(n)R′ groups; n is 1to 100 inclusive; R′ is H or aryl or C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl orC₁-C₃₀ alkynyl; R₁ is selected from the group consisting of H, C₁-C₃₀alkyl, C₁-C₃₀ alkenyl and C₁-C₃₀ alkynyl, said alkyl, alkenyl, oralkynyl being optionally substituted with one or more groupsindependently selected from the group consisting of halogen atoms,hydroxyl groups, C₁-C₃₀ alkyl groups, C₁-C₃₀ alkoxy groups, andO(CH₂CH₂O)_(m)R″ groups; m is 1 to 100 inclusive; R″ is H or aryl orC₁-C₃₀ alkyl, C₁-C₃₀ alkenyl or C₁-C₃₀ alkynyl; R₂ is selected from thegroup consisting of H, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl and C₁-C₃₀ alkynyl,said alkyl, alkenyl, or alkynyl being optionally substituted with one ormore groups independently selected from the group consisting of halogenatoms, hydroxyl groups, C₁-C₃₀ alkyl groups, C₁-C₃₀ alkoxy groups, andO(CH₂CH₂O)_(p)R′″ groups; p is 1 to 100 inclusive; and R′″ is hydrogen,aryl, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl or C₁-C₃₀ alkynyl. In certainembodiments, R may be a C₉-C₅₀ branched alkoxy group.

In certain embodiments, the present invention relates to theaforementioned fullerene-derived ketolactam, wherein X is H or alkyl; R₁is C₁₀-C₂₄ alkyl; and R₂ is CH₃.

In certain embodiments, the present invention relates to theaforementioned fullerene-derived ketolactam, wherein X is H; R₁ is a C₂₂alkyl; and R₂ is CH₃.

In certain embodiments, the present invention relates to theaforementioned fullerene-derived ketolactam, wherein X is H; R₁ is a C₁₆alkyl; and R₂ is CH₃.

In certain embodiments, X is selected from the group consisting of H,C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl, C₁-C₅₀ alkynyl, aryl, and heteroaryl, saidalkyl, alkenyl, alkynyl, aryl, or heteroaryl being optionallysubstituted with one or more groups independently selected from thegroup consisting of halogen atoms, hydroxy groups, C₁-C₅₀ alkyl groups,C₁-C₅₀ alkoxy groups, and O(CH₂CH₂O)_(n)R′ groups; n is 1 to 100inclusive; R′ is H or aryl or C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl or C₁-C₅₀alkynyl; R₁ is selected from the group consisting of H, C₁-C₅₀ alkyl,C₁-C₅₀ alkenyl and C₁-C₅₀ alkynyl, said alkyl, alkenyl, or alkynyl beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxy groups, C₁-C₅₀ alkylgroups, C₁-C₅₀ alkoxy groups, and O(CH₂CH₂O)_(m)R″ groups; m is 1 to 100inclusive; R″ is H or aryl or C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl or C₁-C₅₀alkynyl; R₂ is selected from the group consisting of H, C₁-C₅₀ alkyl,C₁-C₅₀ alkenyl and C₁-C₅₀ alkynyl, said alkyl, alkenyl, or alkynyl beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxy groups, C₁-C₅₀ alkylgroups, C₁-C₅₀ alkoxy groups, and O(CH₂CH₂O)_(p)R′″ groups; p is 1 to100 inclusive; and R′″ is hydrogen, aryl, C₁-C₅₀ alkyl, C₁-C₅₀ alkenylor C₁-C₅₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀ branchedalkoxy group.

In other embodiments, X is H or alkyl; R₁ is C₁₀-C₂₄ alkyl; and R₂ isCH₃.

In still other embodiments, X is H; R₁ is a C₂₂ alkyl; and R₂ is CH₃.

In yet other embodiments, X is H; R₁ is a C₁₆ alkyl; and R₂ is CH₃.

Formula IV

Another aspect of the present invention relates to a fullerene-derivedketolactam selected from the group consisting of C₆₀-derived ketolactamcompounds of formula IV:

or compounds of formula IV wherein one or more additional addends arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof, wherein n is 1 to 30 inclusive; R is selectedfrom the group consisting of C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl, C₁-C₃₀alkynyl, aryl, and heteroaryl, said alkyl, alkenyl, aryl, heteroaryl, oralkynyl being optionally substituted with one or more groupsindependently selected from the group consisting of halogen atoms,hydroxyl groups, C₁-C₃₀ alkyl groups, C₁-C₃₀ alkoxy groups, andO(CH₂CH₂O)_(m)R′ groups; m is 1 to 100 inclusive; and R′ is hydrogen,aryl, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl or C₁-C₃₀ alkynyl. In certainembodiments, R may be a C₉-C₅₀ branched alkoxy group.

In certain embodiments, n is 1 to 30 inclusive; R is selected from thegroup consisting of C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl, C₁-C₅₀ alkynyl, aryl,and heteroaryl, said alkyl, alkenyl, aryl, heteroaryl, or alkynyl beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxy groups, C₁-C₅₀ alkylgroups, C₁-C₅₀ alkoxy groups, and O(CH₂CH₂O)_(m)R′ groups; m is 1 to 100inclusive; and R′ is hydrogen, aryl, C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl orC₁-C₅₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀ branchedalkoxy group.

Formula V

Another aspect of the present invention relates to a fullerene-derivedketolactam selected from the group consisting of C₆₀-derived ketolactamcompounds of formula V:

or compounds of formula V wherein one or more additional addends arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof, wherein n is 2 to 30 inclusive; R is selectedfrom the group consisting of H, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl, C₁-C₃₀alkynyl, aryl, and heteroaryl, said alkyl, alkenyl, aryl, heteroaryl, oralkynyl being optionally substituted with one or more groupsindependently selected from the group consisting of halogen atoms,hydroxyl groups, C₁-C₃₀ alkyl groups, C₁-C₃₀ alkoxy groups, andO(CH₂CH₂O)_(m)R′ groups; m is 1 to 100 inclusive; and R′ is hydrogen,aryl, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl or C₁-C₃₀ alkynyl. In certainembodiments, R may be a C₉-C₅₀ branched alkoxy group.

In certain embodiments, n is 2 to 30 inclusive; R is selected from thegroup consisting of H, C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl, C₁-C₅₀ alkynyl,aryl, and heteroaryl, said alkyl, alkenyl, aryl, heteroaryl, or alkynylbeing optionally substituted with one or more groups independentlyselected from the group consisting of halogen atoms, hydroxy groups,C₁-C₅₀ alkyl groups, C₁-C₅₀ alkoxy groups, and O(CH₂CH₂O)_(m)R′ groups;m is 1 to 100 inclusive; and R′ is hydrogen, aryl, C₁-C₅₀ alkyl, C₁-C₅₀alkenyl or C₁-C₅₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀branched alkoxy group.

Formula VI

Another aspect of the present invention relates to a fullerene-derivedketolactam selected from the group consisting of C₆₀-derived ketolactamcompounds of formula VI:

or compounds of formula V wherein one or more additional addends arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof, wherein n is 2 to 30 inclusive; m is 1 to 100inclusive; p is 2 or 3; R is independently selected from the groupconsisting of H, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl, C₁-C₃₀ alkynyl, aryl, andheteroaryl, said alkyl, alkenyl, aryl, heteroaryl, or alkynyl beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxyl groups, C₁-C₃₀alkyl groups, C₁-C₃₀ alkoxy groups, and O(CH₂CH₂O)_(q)R′ groups; q is 1to 100 inclusive; and R′ is hydrogen, aryl, C₁-C₃₀ alkyl, C₁-C₃₀ alkenylor C₁-C₃₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀ branchedalkoxy group.

Another aspect of the present invention relates to a fullerene-derivedketolactam selected from the group consisting of C₆₀-derived ketolactamcompounds of formula VI:

or compounds of formula VI wherein one or more additional addends arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof, wherein n is 2 to 30 inclusive; m is 1 to 100inclusive; p is 2 or 3; R is —C(O)—X; X is selected from the groupconsisting of H, C₁-C₃₀ alkyl, C₁-C₃₀ alkenyl, C₁-C₃₀ alkynyl, aryl, andheteroaryl, said alkyl, alkenyl, alkynyl, aryl, or heteroaryl beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxyl groups, C₁-C₃₀alkyl groups, C₁-C₃₀ alkoxy groups, and O(CH₂CH₂O)_(q)R′ groups; q is 1to 100 inclusive; and R′ is hydrogen, aryl, C₁-C₃₀ alkyl, C₁-C₃₀ alkenylor C₁-C₃₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀ branchedalkoxy group.

In certain embodiments, the present invention relates to theaforementioned fullerene-derived ketolactam, wherein the compound isbased on C₆₀. In certain embodiments, the present invention relates tothe aforementioned fullerene-derived ketolactam, wherein the compound isbased on C₇₀. In certain embodiments, the present invention relates tothe aforementioned fullerene-derived ketolactam, wherein the compound isbased on C₇₆. In certain embodiments, the present invention relates tothe aforementioned fullerene-derived ketolactam, wherein the compound isbased on C₇₈. In certain embodiments, the present invention relates tothe aforementioned fullerene-derived ketolactam, wherein the compound isbased on C₈₄. In certain embodiments, the present invention relates tothe aforementioned fullerene-derived ketolactam, wherein the compound isbased on C₉₀.

In other embodiments, n is 2 to 30 inclusive; m is 1 to 100 inclusive; pis 2 or 3; R is independently selected from the group consisting of H,C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl, C₁-C₅₀ alkynyl, aryl, and heteroaryl, saidalkyl, alkenyl, aryl, heteroaryl, or alkynyl being optionallysubstituted with one or more groups independently selected from thegroup consisting of halogen atoms, hydroxy groups, C₁-C₅₀ alkyl groups,C₁-C₅₀ alkoxy groups, and O(CH₂CH₂O)_(q)R′ groups; q is 1 to 100inclusive; and R′ is hydrogen, aryl, C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl orC₁-C₅₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀ branchedalkoxy group.

In certain other embodiments, n is 2 to 30 inclusive; m is 1 to 100inclusive; p is 2 or 3; R is —C(O)—X; X is selected from the groupconsisting of H, C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl, C₁-C₅₀ alkynyl, aryl, andheteroaryl, said alkyl, alkenyl, alkynyl, aryl, or heteroaryl beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxy groups, C₁-C₅₀ alkylgroups, C₁-C₅₀ alkoxy groups, and O(CH₂CH₂O)_(q)R′ groups; q is 1 to 100inclusive; and R′ is hydrogen, aryl, C₁-C₅₀ alkyl, C₁-C₅₀ alkenyl orC₁-C₅₀ alkynyl. In certain embodiments, R may be a C₉-C₅₀ branchedalkoxy group.

Other Fullerene Derivatives

In certain embodiments, the present invention relates to theaforementioned fullerene-derived ketolactam, wherein one or moreadditional addends are bonded to the fullerene cage. In certainembodiments, the present invention relates to the aforementionedfullerene-derived ketolactam, wherein said additional addends aremethano-bridges, pyrrolidines, epoxides, or a mixture thereof.

In certain embodiments, the present invention relates to theaforementioned methano-bridge adducts (also referred to asmethanofullerene derivatives). An example of a methanofullerenederivative is a methanofullerene having the general structure:

The —C(X)(Y)— group is bonded to the fullerene via a methano-bridge,which may be obtained through the well-known diazoalkane additionchemistry (W. Andreoni (ed.), The Chemical Physics of Fullerenes 10 (and5) Years Later, 257-265, Kluwer, 1996.). X and Y are aryl, alkyl, orother chemical moieties which can be suitably bonded via the diazoalkaneaddition either by modification of the diazoalkane precursor or afterthe diazoalkane addition by modification of the fullerene derivative. Inthe mono-adduct derivative z is 1; in the bis-adduct derivative, z is 2,and so on.

One example is the molecule where X is an un-substituted aryl, and Y isbutyric-acid-methyl-ester. This molecule is commonly termedphenyl-C_(n)-butyric-acid-methyl-ester (PCBM):

Another example is the molecule where X is a thiophenyl, and Y isbutyric-acid-methyl-ester. This molecule is commonly termedthienyl-C_(n)-butyric-acid-methyl-ester ([C_(n)]ThCBM):

In the two examples above, n represents the number of carbons comprisingthe fullerene and is 60, 70, 76, 78, 84, 90, or greater.

In certain embodiments, the present invention relates to theaforementioned pyrrolidine fullerene derivatives. One example is thePrato fullerene derivative, represented by the general structure:

wherein

C_(n) is a fullerene bonded to —C(R₄R₅)—N(R₃)—C(R₁R₂)—;

n is 60, 70, 76, 78, 84, 90, or greater;

R₁ is optionally substituted aryl or aralkyl;

R₂, R₃, R₄, and R₅ are independently optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted heteroalkyl,optionally substituted heterocycloalkyl, optionally substituted alkenyl,or optionally substituted aralkyl; and

z is 1 to 6.

In certain embodiments, the present invention relates to theaforementioned epoxides, wherein a fullerene, fullerene derivative, orfullerene-derived ketolactam has one or more epoxides bonded to thefullerene cage or fullerene-derived ketolactam, as depicted in thestructures below. Such derivatives may be used in formulations as a soleingredient, or as an additive to formulations comprising one or morefullerenes, fullerene derivatives, or fullerene-derived ketolactams asactives. The fullerene, fullerene derivative or fullerene-derivedketolactam to which one or more epoxides are bonded may be C₆₀, C₇₀,C₇₆, C₇₈, C₈₄, or C₉₀ and m may be about 1 to about 20. Such epoxidesact to quench the photoexcited states of a fullerene, fullerenederivative, or fullerene-derived ketolactam, and thus may be used as anadditive in the range of 0.001% (wt.) to 20% (wt.) to a formulation, forexample useful in skin care, comprising one or more fullerenes,fullerene derivatives, or fullerene-derived ketolactams. One or more ofthe epoxides described herein may also be used as an antioxidant activealone, in the range of 0.001% (wt.) to 20% (wt.), 0.01% (wt.) to 10%(wt.), 0.1% (wt.) to 0.5% (wt.) in a skin care formulation as describedherein. Without intending to be limiting, examples of epoxides bonded tothe cage of a fullerene, fullerene-derived ketolactam, and fullerenederivatives are depicted below.

Another aspect of the present invention relates to a cosmetic ordermatological composition comprising: at least one fullerene-derivedketolactam selected from the aforementioned fullerene-derivedketolactams (i.e., C₆₀-derived ketolactam compounds of formulas I-VI,compounds of formula I-VI wherein one or more additional adducts arebonded to the fullerene cage, and the corresponding C₇₀, C₇₆, C₇₈, C₈₄,or C₉₀ analogs thereof); and a cosmetically or dermatologicallyacceptable carrier.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, furthercomprising one or more components selected from the group consisting ofabrasives, absorbents, aesthetic components, such as fragrances,pigments, colorings, essential oils, skin sensates, astringents, cloveoil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witchhazel distillate, anti-acne agents, anti-caking agents, antifoamingagents, antimicrobial agents, iodopropyl butylcarbamate, antioxidants,binders, biological additives, buffering agents, bulking agents,chelating agents, chemical additives, colorants, cosmetic astringents,cosmetic biocides, denaturants, drug astringents, external analgesics,film formers or materials, polymers for aiding the film-formingproperties and substantivity of the composition, copolymer of eicoseneand vinyl pyrrolidone, opacifying agents, pH adjusters, propellants,reducing agents, sequestrants, skin bleaching and lightening agents,skin-conditioning agents, skin soothing agents or derivatives, healingagents and derivatives, skin treating agents, thickeners, vitamins, andderivatives thereof.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, furthercomprising lavender oil.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein theconcentration of said lavender oil in said composition is between about0.00001% (wt.) and about 0.001% (wt.).

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, furthercomprising at least two fullerene-derived ketolactams selected from theaforementioned fullerene-derived ketolactams (i.e., C₆₀-derivedketolactam compounds of formulas I-VI, compounds of formula I-VI whereinone or more additional adducts are bonded to the fullerene cage, and thecorresponding C₇₀, C₇₆, C₇₈, C₈₄, or C₉₀ analogs thereof).

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein thecosmetic or dermatologically acceptable carrier is selected from thegroup consisting of natural oils, synthetic oils, waxes, and wax-esters.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein thecomposition has an absorbance value at wavelength 570 nm of greater thanabout 0.1.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein thecomposition has an absorbance value at wavelength 570 nm of greater thanabout 0.25.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein thecomposition has an absorbance value at wavelength 570 nm of greater thanabout 0.5.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein thecosmetic or dermatologically acceptable carrier is an emulsion selectedfrom the group consisting of oil-in-water emulsions, water-in-oilemulsions, water-in-oil-in-water emulsions, and oil-in-water-in-siliconeemulsions.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein thecosmetic or dermatologically acceptable carrier is a single, liquidphase.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein thecosmetic or dermatologically acceptable carrier is a single-phase,liquid, oily carrier.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein thecosmetic or dermatologically acceptable carrier is derived from plants.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein thecosmetic or dermatologically acceptable carrier is grape seed oil.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein saidfullerene-derived ketolactam is dissolved in the cosmetic ordermatologically acceptable carrier.

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein theconcentration of said fullerene-derived ketolactam in said compositionis between about 0.001% (wt.) and about 20% (wt.).

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein theconcentration of said fullerene-derived ketolactam in said compositionis between about 0.01% (wt.) and about 10% (wt.).

In certain embodiments, the present invention relates to theaforementioned cosmetic or dermatological composition, wherein theconcentration of said fullerene-derived ketolactam in said compositionis between about 0.1% (wt.) and about 1% (wt.).

Another aspect of the present invention relates to the use of anaforementioned fullerene-derived ketolactam (i.e., C₆₀-derivedketolactam compounds of formulas I-VI, compounds of formula I-VI whereinone or more additional addends are bonded to the fullerene cage, and thecorresponding C₇₀, C₇₆, C₇₈, C₈₄, or C₉₀ analogs thereof) to scavengefree radicals.

Another aspect of the present invention relates to the use of anaforementioned fullerene-derived ketolactam (i.e., C₆₀-derivedketolactam compounds of formulas I-VI, compounds of formula I-VI whereinone or more additional addends are bonded to the fullerene cage, and thecorresponding C₇₀, C₇₆, C₇₈, C₈₄, or C₉₀ analogs thereof) asantioxidants.

Another aspect of the present invention relates to the use of anaforementioned fullerene-derived ketolactam (i.e., C₆₀-derivedketolactam compounds of formulas I-VI, compounds of formula I-VI whereinone or more additional addends are bonded to the fullerene cage, and thecorresponding C₇₀, C₇₆, C₇₈, C₈₄, or C₉₀ analogs thereof) as internal ortopical anti-inflammatory agents in animals or humans.

Another aspect of the present invention relates to the use of anaforementioned fullerene-derived ketolactam (i.e., C₆₀-derivedketolactam compounds of formulas I-VI, compounds of formula I-VI whereinone or more additional addends are bonded to the fullerene cage, and thecorresponding C₇₀, C₇₆, C₇₈, C₈₄, or C₉₀ analogs thereof) on the skin ofanimals or humans.

Another aspect of the present invention relates to the use of anaforementioned fullerene-derived ketolactam (i.e., C₆₀-derivedketolactam compounds of formulas I-VI, compounds of formula I-VI whereinone or more additional addends are bonded to the fullerene cage, and thecorresponding C₇₀, C₇₆, C₇₈, C₈₄, or C₉₀ analogs thereof) for theprevention, remediation, and/or to improve the appearance ofinflammatory conditions of the skin in animals or humans.

In certain embodiments, the present invention relates to theaforementioned use, wherein the inflammatory condition is psoriasis,eczema, rosacea, sun-burn, allergic response, sepsis, dermatomyositis,radiation induced erythema, chemically induced erythema, or laserinduced erythema.

Another aspect of the present invention relates to the use of anaforementioned fullerene-derived ketolactam (i.e., C₆₀-derivedketolactam compounds of formulas I-VI, compounds of formula I-VI whereinone or more additional addends are bonded to the fullerene cage, and thecorresponding C₇₀, C₇₆, C₇₈, C₈₄, or C₉₀ analogs thereof) to improve theappearance of acne in humans, for the prevention of acne in humans, forthe remediation of acne in humans, or for any combination thereof.

Certain Additional Compositions of the Invention

In certain embodiments, the present invention relates to a C_(x)fullerene-derived ketolactam represented by formula I:

wherein x is 60, 70, 76, 78, 84, or 90; R is a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal,optionally substituted with one aryl group, heteroaryl group, halogenatom, hydroxyl group, a branched or unbranched, with unsaturation fromzero up to maximal alkoxy group, or a branched or unbranched, withunsaturation from zero up to maximal alkanoyloxy group, said aryl orheteroaryl being optionally substituted with a halogen atom, a hydroxylgroup, a C₁-C₅₀ hydrocarbon chain, branched or unbranched, withunsaturation from zero up to maximal alkyl group, a C₁-C₅₀, linearalkoxy group, a C₉-C₅₀ branched alkoxy group, a C₁-C₅₀, branched orunbranched, with unsaturation from one up to maximal alkoxy group, aC₁-C₅₀, branched or unbranched, with unsaturation from zero up tomaximal alkanoyloxy group, or a —O(CH₂CH₂O)_(n)R′ group; n is 1 to 100inclusive; and R′ is H, aryl, or a C₁-C₅₀ hydrocarbon chain, branched orunbranched, with unsaturation from zero up to maximal.

In certain other embodiments, the present invention relates to a C_(x)fullerene-derived ketolactam represented by formula I:

wherein x is 60, 70, 76, 78, 84, or 90; R is a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal,optionally substituted with one aryl group, heteroaryl group, halogenatom, hydroxyl group, a branched or unbranched, with unsaturation fromzero up to maximal alkoxy group, or a branched or unbranched, withunsaturation from zero up to maximal alkanoyloxy group, said aryl orheteroaryl being optionally substituted with two or more groups,independently selected from the group consisting of halogen atoms,hydroxyl groups, C₁-C₅₀ hydrocarbon chains, branched or unbranched, withunsaturation from zero up to maximal alkyl group, C₁-C₅₀, branched orunbranched, with unsaturation from zero up to maximal alkoxy groups,C₁-C₅₀, branched or unbranched, with unsaturation from zero up tomaximal alkanoyloxy groups, or —O(CH₂CH₂O)_(n)R′ groups; n is 1 to 100inclusive; and R′ is H, aryl, or a C₁-C₅₀ hydrocarbon chain, branched orunbranched, with unsaturation from zero up to maximal. In certainembodiments, R may be a C₉-C₅₀ branched alkoxy group.

In still other embodiments, the present invention relates to a C_(x)fullerene-derived ketolactam represented by formula I:

wherein x is 60, 70, 76, 78, 84, or 90; R is a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal,optionally substituted with two or more aryl groups, heteroaryl groups,halogen atoms, hydroxyl groups, branched or unbranched, withunsaturation from zero up to maximal alkoxy groups, or branched orunbranched, with unsaturation from zero up to maximal alkanoyloxygroups, said aryls or heteroaryls being optionally substituted with oneor more groups, independently selected from the group consisting ofhalogen atoms, hydroxyl groups, C₁-C₅₀ hydrocarbon chains, branched orunbranched, with unsaturation from zero up to maximal alkyl group,C₁-C₅₀, branched or unbranched, with unsaturation from zero up tomaximal alkoxy groups, C₁-C₅₀, branched or unbranched, with unsaturationfrom zero up to maximal alkanoyloxy groups, or —O(CH₂CH₂O)_(n)R′ groups;n is 1 to 100 inclusive; and R′ is H, aryl, or a C₁-C₅₀ hydrocarbonchain, branched or unbranched, with unsaturation from zero up tomaximal. In certain embodiments, R may be a C₉-C₅₀ branched alkoxygroup.

In yet other embodiments, the present invention relates to a C_(x)fullerene-derived ketolactam represented by formula I:

wherein x is 60, 70, 76, 78, 84, or 90; R is aryl or heteroaryl, saidaryl or heteroaryl being optionally substituted with one or more groupsindependently selected from the group consisting of halogen atoms,hydroxyl groups, C₁-C₅₀ linear or branched, with unsaturation from zeroup to maximal alkyl groups, C₁-C₅₀ linear or branched, with unsaturationfrom zero up to maximal alkoxy groups, C₁-C₅₀ branched or unbranched,with unsaturation from zero up to maximal alkanoyloxy groups, or—O(CH₂CH₂O)_(n)R′ groups; n is 1 to 100 inclusive; and R′ is H, aryl, ora C₁-C₅₀ hydrocarbon chain, branched or unbranched, with unsaturationfrom zero up to maximal. In certain embodiments, R may be a C₉-C₅₀branched alkoxy group.

In other embodiments, the present invention relates to a C_(x)fullerene-derived ketolactam represented by formula II:

wherein x is 60, 70, 76, 78, 84, or 90; Y is a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal; R isaryl or heteroaryl, said aryl or heteroaryl being optionally substitutedwith one or more groups independently selected from the group consistingof halogen atoms, hydroxyl groups, C₁-C₅₀ linear or branched, withunsaturation from zero up to maximal alkyl groups, C₁-C₅₀ linear orbranched, with unsaturation from zero up to maximal alkoxy groups,C₁-C₅₀ branched or unbranched, with unsaturation from zero up to maximalalkanoyloxy groups, or —O(CH₂CH₂O)_(n)R′ groups; n is 1 to 100inclusive; and R′ is hydrogen, aryl, or a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal. Incertain embodiments, R may be a C₉-C₅₀ branched alkoxy group.

In some embodiments, the present invention relates to the compoundrepresented by formula III:

wherein x is 60, 70, 76, 78, 84, or 90; X is H or a C₁-C₅₀ linear orbranched, with unsaturation from zero up to maximal alkyl group; R₁ isH, a C₁-C₅₀ linear or branched, with unsaturation from zero up tomaximal alkyl group, or O(CH₂CH₂O)_(m)R″; m is 1 to 100 inclusive; R″ isH, aryl, or a C₁-C₅₀ hydrocarbon chain, branched or unbranched, withunsaturation from zero up to maximal; R₂ is H, a C₁-C₅₀ linear orbranched, with unsaturation from zero up to maximal alkyl group, orO(CH₂CH₂O)_(p)R′″; p is 1 to 100 inclusive; and R′″ is H, aryl, or aC₁-C₅₀ hydrocarbon chain, branched or unbranched, with unsaturation fromzero up to maximal. In some embodiments, X is H or alkyl; R₁ is C₁₀-C₂₄alkyl; and R₂ is CH₃. In some embodiments, X is H; R₁ is a C₂₂ alkyl;and R₂ is CH₃. In some embodiments, X is H; R₁ is a C₁₆ alkyl; and R₂ isCH₃. In certain embodiments, R may be a C₉-C₅₀ branched alkoxy group.

In other embodiments, the present invention relates to a C_(x)fullerene-derived ketolactam represented by formula IV:

wherein x is 60, 70, 76, 78, 84, or 90; Y is a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal; R isselected from the group consisting of H, a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal, aryl,and heteroaryl, said hydrocarbon chain, aryl, or heteroaryl, beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxyl groups, C₁-C₅₀linear or branched, with unsaturation from zero up to maximal alkylgroups, C₁-C₅₀ linear or branched, with unsaturation from zero up tomaximal alkoxy groups, C₁-C₅₀ branched or unbranched, with unsaturationfrom zero up to maximal alkanoyloxy groups, or —O(CH₂CH₂O)_(n)R′ groups;n is 1 to 100 inclusive; and R′ is hydrogen, aryl, or a C₁-C₅₀hydrocarbon chain, branched or unbranched, with unsaturation from zeroup to maximal. In certain embodiments, R may be a C₉-C₅₀ branched alkoxygroup.

In certain other embodiments, the present invention relates to a C_(x)fullerene-derived ketolactam represented by formula V:

wherein x is 60, 70, 76, 78, 84, or 90; Y is a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal; R isselected from the group consisting of H, a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal, aryl,and heteroaryl, said hydrocarbon chain, aryl, or heteroaryl, beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxyl groups, C₁-C₅₀linear or branched, with unsaturation from zero up to maximal alkylgroups, C₁-C₅₀ linear or branched, with unsaturation from zero up tomaximal alkoxy groups, C₁-C₅₀ branched or unbranched, with unsaturationfrom zero up to maximal alkanoyloxy groups, or —O(CH₂CH₂O)_(n)R′ groups;n is 1 to 100 inclusive; and R′ is hydrogen, aryl, or a C₁-C₅₀hydrocarbon chain, branched or unbranched, with unsaturation from zeroup to maximal. In certain embodiments, R may be a C₉-C₅₀ branched alkoxygroup.

In yet other embodiments, the present invention relates to a C_(x)fullerene-derived ketolactam represented by formula VI:

wherein x is 60, 70, 76, 78, 84, or 90; Y is a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal; m is1 to 100 inclusive; p is 2 or 3; R is independently selected from thegroup consisting of H, a C₁-C₅₀ hydrocarbon chain, branched orunbranched, with unsaturation from zero up to maximal, aryl, andheteroaryl, said hydrocarbon chain, aryl, or heteroaryl, beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxyl groups, C₁-C₅₀linear or branched, with unsaturation from zero up to maximal alkylgroups, C₁-C₅₀ linear or branched, with unsaturation from zero up tomaximal alkoxy groups, C₁-C₅₀ branched or unbranched, with unsaturationfrom zero up to maximal alkanoyloxy groups, or —O(CH₂CH₂O)_(n)R′ groups;n is 1 to 100 inclusive; and R′ is hydrogen, aryl, or a C₁-C₅₀hydrocarbon chain, branched or unbranched, with unsaturation from zeroup to maximal. In certain embodiments, R may be a C₉-C₅₀ branched alkoxygroup.

In other embodiments, the present invention relates to a C_(x)fullerene-derived ketolactam represented by formula VI:

wherein x is 60, 70, 76, 78, 84, or 90; Y is a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal; m is1 to 100 inclusive; p is 2 or 3; R is —C(O)—X; X is selected from thegroup consisting of H, a C₁-C₅₀ hydrocarbon chain, branched orunbranched, with unsaturation from zero up to maximal, aryl, andheteroaryl, said hydrocarbon chain, aryl, or heteroaryl, beingoptionally substituted with one or more groups independently selectedfrom the group consisting of halogen atoms, hydroxyl groups, C₁-C₅₀linear or branched, with unsaturation from zero up to maximal alkylgroups, C₁-C₅₀ linear or branched, with unsaturation from zero up tomaximal alkoxy groups, C₁-C₅₀ branched or unbranched, with unsaturationfrom zero up to maximal alkanoyloxy groups, or —O(CH₂CH₂O)_(n)R′ groups;n is 1 to 100 inclusive; and R′ is hydrogen, aryl, or a C₁-C₅₀hydrocarbon chain, branched or unbranched, with unsaturation from zeroup to maximal. In certain embodiments, R may be a C₉-C₅₀ branched alkoxygroup.

EXEMPLIFICATION

The present description is further illustrated by the followingexamples, which should not be construed as limiting in any way.

Example 1 Synthesis of Fullerene-derived Ketolactam Derivative HG2-V1

The fullerene-derived ketolactam derivative HG2-V1 was synthesized bythe route as depicted in FIG. 9. The synthesis is based on proceduresthat have been published in literature for comparable compounds (see,for example, a) P. Chritchley and G. J. Clarkson, Organic andBiomolecular Chemistry 2003, 1, 4148; and b) C. J. Brabec et al.,Advanced Functional Materials 2001, 11, 374).

[a] Synthesis of 4-hexadecyloxy-3-methoxy-benzaldehyde. A mixture of3.05 g of vanilline, 6.11 g of hexadecylbromide, 30 mg oftetrabutylammonium iodide and 3.10 g of potassium carbonate in 35 mL ofDMF was heated at 65° C. under an N₂ atmosphere for 66 h. The reactionmixture was cooled down to room temperature and mixed with 120 mL ofwater. The aqueous layer was extracted with ether (1×150 mL,subsequently 3×50 mL). The organic layers were combined and washedsubsequently with a saturated NaHCO₃ solution (25 mL), water (25 mL),and brine (25 mL). Drying over Na₂SO₄ and removal of the solvent invacuo gave 7.32 g of crude product. This was recrystallized from 50 mLof methanol to give 6.93 g of 4-hexadecyloxy-3-methoxy-benzaldehyde as awhite powder. ¹H NMR (300 MHz, CDCl₃): δ 9.85 (s, 1H); 7.45-7.40 (m,2H); 6.96 (d, 1H, J=8.0 Hz); 4.10 (t, 2H, J=6.8 Hz); 3.93 (s, 3H);1.92-1.82 (m, 2H); 1.52-1.20 (m, 26H); 0.88 (t, 3H, J=7.0 Hz) ppm. ¹³CNMR (75 MHz, CDCl₃): δ 190.90; 154.21; 149.86; 129.86; 126.80; 111.36;109.26; 69.20; 56.03; 31.91; 29.68 (large signal); 29.58; 29.52; 29.34;28.90; 25.88; 22.69; 14.11 ppm. IR (KBr, cm⁻¹): 3003 (m); 2913 (s); 2849(s); 1676 (s); 1597 (m); 1585 (s); 1512 (s) 1273 (m); 1239 (m).

[b] Synthesis of 4-hexadecyloxy-3-methoxy-benzyl alcohol. To a solutionof 3.01 g 4-hexadecyloxy-3-methoxy-benzaldehyde in a mixture of 25 mL ofmethanol and 50 mL of tetrahydrofuran was added 310 mg of NaBH₄. Thereaction was stirred overnight and quenched it into 350 mL of ice water.The product was isolated by filtration and recrystallized from methanol.This gave 2.63 g of 4-hexadecyloxy-3-methoxy-benzyl alcohol as a finewhite powder. ¹H NMR (300 MHz, CDCl₃): δ 6.93 (s, 1H); 6.90-6.83 (m,2H); 4.62 (s, 2H); 4.00 (t, 2H, J=6.9 Hz); 3.88 (s, 3H); 1.89-1.78 (m,2H); 1.50-1.22 (m, 26H); 0.88 (t, 3H, J=6.9 Hz) ppm. ¹³C NMR (75 MHz,CDCl₃): δ 149.43; 148.06; 133.46; 119.35; 112.70; 110.82; 69.07; 65.24;55.87; 31.87; 29.63 (large signal); 29.55; 29.52; 29.36; 29.31; 29.10;25.90; 22.64; 14.07 ppm. IR (KBr, cm⁻¹): 3350 (m, br.); 3008 (w); 2953(m); 2917 (m); 2848 (m); 1612 (w); 1590 (m); 1518 (m); 1467 (m); 1254(m); 1237 (m).

[c] Synthesis of 4-hexadecyloxy-3-methoxy-benzyl chloride. To a solutionof 2.55 g of 4-hexadecyloxy-3-methoxy-benzyl alcohol in 40 mL ofdichloromethane was added 1.0 mL of thionyl chloride. The resultingmixture was stirred for 22 h. The reaction was quenched by pouring thesolution into 25 mL of water. The layers were separated and the aqueouslayer was extracted with ether (3×25 mL). The organic layers werecombined, washed twice with brine, and dried over Na₂SO₄. Removal of thesolvents in vacuo gave 3.3 g of a dark oil that solidified uponstanding, giving a brown solid. Recrystallization from acetonitrile gave1.85 g of 4-hexadecyloxy-3-methoxy-benzyl chloride as a light brownpowder. ¹H NMR (300 MHz, CDCl₃): δ 6.93-6.80 (br. m, 3H); 4.57 (s, 2H);4.01 (t, 2H, J=6.8 Hz); 1.87-1.79 (m, 2H); 1.49-1.21 (m, 26H); 0.88 (t,3H, J=6.9 Hz) ppm. ¹³C NMR (50 MHz, CDCl₃): δ 149.50; 148.83; 129.83;121.12; 112.59; 112.18; 69.07; 55.99; 46.70; 31.90; 29.66 (largesignal); 29.57; 29.35; 29.09; 25.92; 22.66; 14.08 ppm. IR (KBr, cm⁻¹):2997 (w); 2917 (m); 2849 (m); 1605 (w); 1591 (w); 1519 (m); 1465 (m);1270 (m); 1240 (m).

[d] Synthesis of 4-hexadecyloxy-3-methoxy-benzyl azide. A mixture of1.78 g of 4-hexadecyloxy-3-methoxy-benzyl chloride, 293 mg of NaN₃ and acatalytic amount of Bu₄NI in 20 mL of DMSO was heated at 60° C. for 42h. The reaction mixture was cooled down to room temperature and mixedwith 75 mL of ice water. The crude product was isolated by filtrationand redissolved in ether (50 mL). This solution was washed with a smallamount of brine and dried over Na₂SO₄. Removal of the solvent in vacuogave 1.72 g of a dark oil that solidified upon standing, giving a brownsolid. Column chromatography (silica gel, petroleum ether/ether 95/5(v/v)) was used to isolate the product. All solutions containing thedesired benzyl azide were combined and the resulting solution wasdecolorized using activated carbon. Drying over Na₂SO₄ and removal ofthe solvents in vacuo gave 1.70 g of 4-hexadecyloxy-3-methoxy-benzylazide as an off-white solid. ¹H NMR (300 MHz, CDCl₃): δ 6.90-6.82 (m,3H); 4.27 (s, 2H); 4.01 (t, 2H, J=6.7 Hz); 3.88 (s, 3H); 1.89-1.79 (m,2H); 1.52-1.21 (m, 26H); 0.88 (t, 3H, J=6.6 Hz) ppm. ¹³C NMR (75 MHz,CDCl₃): δ 149.57; 148.68; 127.63; 120.80; 112.64; 111.75; 69.04; 55.99;54.81; 31.92; 29.69 (large signal); 29.60; 29.40; 29.35; 29.13; 25.94;22.69; 14.13 ppm. IR (KBr, cm⁻¹): 2998 (w); 2916 (m); 2849 (m); 2099(m); 1589 (w); 1517 (m); 1468 (m); 1267 (m); 1238 (m).

[e] Synthesis of HG2-V1. A solution of C₆₀ (2.17 g) in o-dichlorobenzene(450 mL) under N₂ was heated to 150° C. Subsequently,4-hexadecyloxy-3-methoxy-benzyl azide (1.23 g) was added at once and theresulting mixture was heated to 170° C., and kept at this temperaturefor approximately 2.5 h. It was cooled down to room temperature andconcentrated in vacuo.

The reaction mixture was redissolved in 200 mL of a 1:1 mixture (v/v) ofp-xylene and petroleum ether (Bp 80-110° C.) and put on a silica gelcolumn (prepared with p.e. 80-110). The desired azafulleroid wasisolated by chromatography using p-xylene/p.e. 80-110 (1:2 (v/v)). Thisgave a mixture of the crude azafulleroid and C₆₀ in a 57/43 ratio, whichwas directly used in the next step of the synthesis.

The crude azafulleroid was redissolved in o-dichlorobenzene (400 mL).This solution was placed in a large 3-necked flask fitted with a gasinlet, a condenser, and a thermometer. Oxygen was bubbled through thesolution, and the reaction mixture was illuminated with a 400 W sodiumlamp, with stirring. The conversion of the azafulleroid to thefullerene-derived ketolactam derivative was monitored by HPLC. Theconversion was complete after irradiating for 23 h, during which timethe temperature rose to 46° C. The reaction mixture was concentrated invacuo, and the product was purified by column chromatography (silicagel, toluene. The product was suspended in pentane and isolated bycentrifugation. Subsequently, it was washed 2× with pentane. Drying invacuo gave 0.69 g product as a black solid. Of this material, 530 mg waschromatographed and purified a second time, as described above. Thisgave 435 mg pure HG2-V1 as black, crystalline material. ¹H NMR (300 MHz,CDCl₃): δ 7.11 (d, 1H, J=1.5 Hz); 7.08-7.03 (m, 1H); 6.82 (d, 1H, J=8.1Hz); 6.34 (d, 1H, J=15.0 Hz); 5.36 (d, 1H, J=14.7 Hz); 3.98 (t, 2H,J=6.9 Hz); 3.86 (s, 3H); 1.84-1.78 (m, 2H); 1.50-1.22 (m, 26H); 0.88 (t,3H, J=7.1 Hz) ppm. IR (KBr, cm⁻¹): 2922 (s); 2850 (s); 2337 (w); 1728(s); 1688 (s); 1515 (m); 1463 (m); 1261 (m); 1036 (m); 769 (m); 522 (m).

Example 2 Synthesis of Fullerene-derived Ketolactam HG2-V2

HG2-V2 (CAS#943912-75-2; CA Index Name:2a-Aza-1,2(2a)-homo-1,9-seco[5,6]fullerene-C₆₀-I_(h)-1,9-dione,2a-[[4-docosyloxy)-3-methoxyphenyl]methyl]was prepared in a method directly analogous to HG2-V1, the onlydifference being the substitution of C₂₂H₄₅Br in place of C₁₆H₃₃Br.Comparable yields were obtained. ¹H NMR (300 MHz, CDCl₃): d 7.11 (d, 1H,J=1.8 Hz); 7.08-7.03 (m, 1H); 6.82 (d, 1H, J=8.4 Hz); 6.34 (d, 1H,J=14.6 Hz); 5.36 (d, 1H, J=15.0 Hz); 3.97 (t, 2H, J=6.8 Hz); 3.86 (s,3H); 1.84-1.78 (m, 2H); 1.50-1.22 (m, 38H); 0.88 (t, 3H, J=6.6 Hz) ppm.IR (KBr, cm⁻¹): 2922 (s); 2851 (s); 2336 (w); 1728 (s); 1688 (s); 1515(m); 1463 (m); 1261 (m); 1037 (m); 769 (m); 522 (m).

Examples 1 and 2 describe the synthesis of two fullerene-derivedketolactam molecules. As described throughout the specification, otherfullerene-derived ketolactam molecules are contemplated. Alsocontemplated are fullerene-derived ketolactam derivative molecules,where one or more addends are chemically bonded to the fullerene cage ofthe fullerene-derived ketolactam. Non-limiting examples of suchfullerene-derived ketolactam derivatives are fullerene-derivedketolactam methano derivatives, fullerene-derived ketolactam pyrrolidinederivatives, and fullerene-derived ketolactam epoxide derivatives.

In some embodiments, the addend may be chemically bonded to a fullerenederived ketolactam. In other embodiments, the addend may be chemicallybonded to a fullerene, which may then be used as a reactant for theproduction of a fullerene-derived ketolactam derivative.

Example 3 Comparison of the ¹O₂ and Superoxide Generation Rate ofFullerene Derivatives and Fullerene-derived Ketolactams: Photo-oxidationof Adamantylideneadamantane

Fullerenes are known to produce ¹O₂ upon illumination by the reactionsequence:

-   Fullerene+light→excited fullerene, singlet-   Excited fullerene, singlet→excited fullerene, triplet-   Excited fullerene, triplet+O₂→fullerene+singlet oxygen (¹O₂)    The ¹O₂ thus generated can react with a fullerene, giving an    oxidized fullerene, or with other molecules that can react with ¹O₂.    One such molecule is adamantylideneadamantane (ad=ad), which is    known to react with ¹O₂, giving a stable 1,2-dioxetane,    adamantylideneadamantane peroxide, as the product (J. H. Wiering a    et al., Tetrahedron Letters 1972, 2, 169). This reaction is depicted    in FIG. 11. This oxidation of ad=ad can be used to monitor the    formation of ¹O₂ by fullerenes or fullerene derivatives.

In a first set of experiments, Phenyl-C₆₁-Butyric-Acid-Methyl-Ester(PCBM,) and HG2-V1 were compared. A dilute solution of ad=ad inchlorobenzene (1.5 mg/mL) containing a small amount of the fullerenederivative was irradiated with a Na lamp, while bubbling air through thesolution. Details are described in Experiments 1 and 2 below. Afterreaction overnight, the solvent was removed in vacuo and the residualmaterial analyzed by ¹H NMR. This showed the formation of the dioxetanecompound, as evidenced from the appearance of a signal at 2.65 ppm. Theamount of adamantylideneadamantane peroxide formed when PCBM was usedwas much larger than that formed when using HG2-V1. Since the molaramounts of fullerene derivative used are comparable, this resultindicates that HG2-V1 generates less ¹O₂ than PCBM. In both cases, mostof the fullerene material had been photobleached after the illumination.

In a second set of experiments, the above reaction was done at a highconcentration (20 mg/mL) of ad=ad, this time using CCl₄ as the solvent.The advantage of CCl₄ is that this solvent does not show any signals in¹H NMR spectra. The high concentration of ad=ad allows for easymeasurements and makes it possible to see small percentages of dioxetanethat are formed. Thus, samples from the reaction can be directlyanalyzed by ¹H NMR, when diluted with, e.g., CDCl₃. This allows formonitoring the formation of the dioxetane compound over time.

The results from these experiments (Experiments 3 and 4 below) show thatthe production of adamantylideneadamantane peroxide proceeds much fasterwith PCBM compared to HG2-V1, and also that more of the dioxetanecompound is produced when using PCBM. The results are depicted in thegraph below. The graph displays the ratio of the peak at 2.65 ppm andthe signal at 2.88 ppm of ad=ad. As before, the fullerenes were oxidizedto a large extent after the reaction, which is why the formation of thedioxetane almost stops at long irradiation times. These results againindicate that HG2-V1 produces less ¹O₂ than PCBM.

[a] Experiment 1. A solution of adamantylideneadamantane (150 mg) andPCBM (4.9 mg) in chlorobenzene (100 mL) was placed in a 3-necked flaskfitted with a thermometer, a gas inlet, a magnetic stir bar, and acondenser. Then, the solution was illuminated (with stirring) for 17 husing a 400 W sodium lamp at close range, while bubbling air through thesolution. During this time, the temperature of the solution rose to 37°C.

The lamp was switched off and the reaction mixture was cooled down andconcentrated in vacuo to give an off-white solid. Subsequently, some ofthis solid material was scraped out using a spatula, dissolved in CDCl₃and investigated by ¹H NMR. This showed the formation of a substantialamount of adamantylideneadamantane peroxide, as evidenced by the broadsignal at 2.65 ppm.

[b] Experiment 2. A solution of adamantylideneadamantane (152 mg) andHG2-V1 (5.8 mg) in chlorobenzene (100 mL) was placed in a 3-necked flaskfitted with a thermometer, a gas inlet, a magnetic stir bar, and acondenser. Then, the solution was illuminated (with stirring) for 16.5 husing a 400 W sodium lamp at close range, while bubbling air through thesolution. During this reaction, the temperature of the solution rose to45° C.

The lamp was switched off and the reaction mixture was cooled down andconcentrated in vacuo to give an off-white solid. Subsequently, some ofthis solid material was scraped out using a spatula, dissolved in CDCl₃and investigated by ¹H NMR. This showed the formation ofadamantylideneadamantane peroxide, as evidenced by the broad signal at2.65 ppm. The relative amount of peroxide formed was, however,considerably smaller than that obtained when using PCBM as the dyegenerating ¹O₂ (see Experiment 1 above).

[c] Experiment 3. A solution of adamantylideneadamantane (403 mg) andPCBM (2.1 mg) in tetrachloromethane (20 mL) was placed in a 3-neckedflask fitted with a thermometer, a gas inlet, a magnetic stir bar, and acondenser. Then, the solution was illuminated (with stirring) using a150 W sodium lamp at close range (˜6 cm distance), while bubbling airthrough the solution. During this reaction, the temperature of thesolution rose to 36° C.

Samples of 150-200 μL were taken from the reaction and diluted with ˜400μL of CDCl₃. Subsequently these solutions were investigated by ¹H NMR.Thus, the formation of adamantylideneadamantane peroxide was monitoredover time, by following the appearance of the signal at 2.65 ppm.

[d] Experiment 4. A solution of adamantylideneadamantane (402 mg) andHG2-V1 (2.7 mg) in tetrachloromethane (20 mL) was placed in a 3-neckedflask fitted with a thermometer, a gas inlet, a magnetic stir bar, and acondenser. Then, the solution was illuminated (with stirring) using a150 W sodium lamp at close range (˜6 cm distance), while bubbling airthrough the solution. During this reaction, the temperature of thesolution rose to 37° C. The (setup of the) equipment used for thisreaction was the same as used in Experiment 3.

Samples of 150-200 μL were taken from the reaction and diluted with ˜400μL of CDCl₃. Subsequently these solutions were investigated by ¹H NMR.Thus, the formation of adamantylideneadamantane peroxide was monitoredover time, by following the appearance of the signal at 2.65 ppm.

At the initial data point of 13 minutes (PCBM) and 14 minutes (HG2-V1),it was observed that both solutions were still clear, with no visiblesolids or color change, indicating that little photobleaching of eithercompound had occurred. The concentrations of each can be assumed to beconstant and equal to the starting concentrations, which were of equalmolarity. Since ad=ad is in large excess, its concentration can also beassumed to be constant. FIG. 12 shows the ratio of the dioxetane productto the ad=ad reactant. It can be seen that much less oxidation productof the ad=ad+singlet oxygen reaction is formed by the HG2-V1 compared toPCBM. As the ad=ad and PCBM or HG2-V1 concentrations can all be assumedto be constant, the ratio of the slopes of the initial rate of formationof the dioxetane product can be used to give a semi-quantitative measureof the overall ¹O₂ generation capacity. Since the extinctioncoefficients of PCBM and HG2-V1 are approximately equal for the visiblewavelengths used (from the Na lamp), then the ratio of the slopes isapproximately equal to the ratio of the net generation of ¹O₂. Takingthis ratio gives the result that the net generation of ¹O₂ of HG2-V1 isabout 0.2-0.3 of the net generation of ¹O₂ of PCBM.

[e] Two beakers were irradiated simultaneously with a UV light source(Philips HB172, fitted with 4 Philips Cleo 15W luminescent tubes;UV-type 3). Beaker 1 contained a mixture of 301.0 mg ofadamantylideneadamantane and 24.9 mg of α-tocopherol (Aldrich, >97%) in100 mL of chlorobenzene. This solution was placed in a 250 mL beaker,which was wrapped with paper and Al-foil to prevent light going throughthe side of the beaker. The solution was stirred magnetically andirradiated 7 hours with a UV lamp (Philips HB172, fitted with 4 PhilipsCleo 15W luminescent tubes; UV-type 3), which was mounted horizontallydirectly above the beakers. The reaction mixture was concentrated invacuo and the resulting solid material was analyzed by ¹H NMRspectroscopy as described above. This showed the formation ofadamantylideneadamantane peroxide, as evidenced by the broad signal at2.65 ppm. The ratio of the integrals of unreactedadamantylideneadamantane (at 2.9 ppm) to adamantylideneadamantaneperoxide was 90:10.

Beaker 2 contained a mixture of 301.2 mg of adamantylideneadamantane and25.0 mg of HG2-V2 in 100 mL of chlorobenzene. This solution was placedin a 250 mL beaker, which was wrapped with paper and Al-foil to preventlight going through the side of the beaker. The solution was stirredmagnetically and irradiated 7 hours with a UV lamp (Philips HB172 fittedwith 4 Philips Cleo 15W luminescent tubes; UV-type 3), which was mountedhorizontally directly above the beakers. The reaction mixture wasconcentrated in vacuo and the resulting solid material was analyzed by¹H NMR spectroscopy as described above. This showed the formation ofadamantylideneadamantane peroxide, as evidenced by the broad signal at2.65 ppm. The ratio of the integrals of unreactedadamantylideneadamantane (at 2.9 ppm) to adamantylideneadamantaneperoxide was 94:6.

This example demonstrates that the net generation of ¹O₂ under UVirradiation, of equal weight percentage formulations, is less for HG2-V2than α-tocopherol.

[f] Two beakers were irradiated simultaneously by natural sunlight.Beaker 2 contained a solution of 300.5 mg of adad and 17.9 mg of PCBM in100 mL of chlorobenzene. This solution was placed in a 250 mL beaker,wrapped with paper and Al-foil to prevent light going through the sideof the beaker. The solution was stirred magnetically and placed outside,in Groningen, The Netherlands, on a sunny day in July, from 13.40 pm to16.30 pm. The resulting solution was put in a brown-glass bottle fortransport. The solvent was removed in vacuo and the resulting solidmaterial was analyzed by ¹H NMR spectroscopy as described above. Thisshowed the formation of adamantylideneadamantane peroxide, as evidencedby the broad signal at 2.65 ppm. The ratio of the integrals of unreactedadamantylideneadamantane (at 2.9 ppm) to adamantylideneadamantaneperoxide was 78:22.

Beaker 2 contained a mixture of 300.7 mg of adad and 8.1 mg of methyleneblue (MB) in 100 mL of chlorobenzene. This solution was placed in a 250mL beaker, wrapped with paper and Al-foil to prevent light going throughthe side of the beaker. The saturated solution was stirred magneticallyand placed outside, in Groningen, The Netherlands, on a sunny day inJuly, from 13.40 pm to 16.30 pm. The resulting solution was placed in abrown-glass bottle for transport. Approximately 10 mL of the reactionmixture was filtered and put aside. The remaining amount wasconcentrated in vacuo and the resulting solid material was analyzed by¹H NMR spectroscopy as described above. This showed the formation ofadamantylideneadamantane peroxide, as evidenced by the broad signal at2.65 ppm. The ratio of the integrals of unreactedadamantylideneadamantane (at 2.9 ppm) to adamantylideneadamantaneperoxide was 56:44.

The end-concentration of MB in the chlorobenzene was determined byUV-Vis spectroscopy, using the above mentioned filtered solution. Thissolution gave an absorbance of A=0.14 at 646 nm (against neatchlorobenzene). The extinction coefficient at 646 nm of MB in pyridineis 8×10⁴ (R. B. McKay, Nature 1966, 210, 296-297), meaning that theconcentration was approximately 1.8×10⁻³ mmol/L, corresponding to 0.67mg/L (compared to 240 mg/L for HG2-V2 above).

This experiment shows that though the ¹O₂ quantum yield of MB is ˜0.5,about half of PCBM (˜1.0), the net generation of ¹O₂ is 250 times higherfor MB than for PCBM on an equimolar basis. The average opticalabsorption between 400 nm and 700 nm is about 10 times higher for MBcompared to PCBM, therefore, MB produces 25 times the amount of ¹O₂ asPCBM on an equal absorption and equimolar basis, though it has a ¹O₂quantum yield half that of PCBM. This demonstrates the effect that thenet ¹O₂ generation of fullerenes is in fact much lower than expected,due to the quenching effects of epoxide reaction products formed by thephotooxidation. Therefore, addition of mono- and multi-epoxidizedfullerenes, fullerene derivatives, or fullerene-derived ketolactams to aformulation can act to minimize the reaction products of thephotoexcited states of the fullerene, fullerene derivative, orfullerene-derived ketolactam.

[g] Generation of superoxide by HG2-V2 was determined. The superoxidetests were based on the trapping of the superoxide radical, O₂ ⁻., byNBT, nitroblue tetrazolium dichloride. The superoxide formed reacts withthe NBT, which is light yellow in aqueous solutions, to form(di)formazan, an intensely blue dye. The absorbance around 550 nm of theformazan can be measured by UV-Vis spectroscopy, which is a measure forthe amount of superoxide formed. For more information see: C. Auclairand E. Voisin, in CRC Handbook of methods for oxygen radical research,R. A. Greenwald, Eds., CRC Press, Boca Raton, Fla., 1985, p 123-132.

This system has been used to show the formation of the superoxideradical by C₆₀-PVP complexes upon irradiation, in a model of abiological environment (Y. Yamakoshi et al., J. Am. Chem. Soc. 2003,125, 12803). In the NBT superoxide test, a blank reaction takes placedue to the NADH initiator used, depending on the exact conditions andreactants used. In the system used by Yamakoshi et al. the blankreaction is present. Therefore, what is actually determined is theadditional formation of superoxide by the compound under investigation.

The C₆₀/PVP experiments as reported in literature were done on a smallscale, using a total volume of only 164 μL. The reaction was scaled to 5mL, so that it can be performed in reagent tubes, with magneticstirring. In all reactions, 600 μL of a 1 mM EDTA solution, 0.60 mL of a2.4 mM NBT solution, and 240 uL of phosphate buffer (pH 7.2,Sigma-Aldrich) were placed in the tube. Subsequently, the followingamounts were added: NADH solution: 100 μL; H₂O: 3.5 mL. The NADHsolution was 1 mg/mL, and prepared by adding 5.0 mL H₂O to a vialcontaining 5 mg of NADH (˜98%, Sigma). Two experiments were performedwith this above preparation. In the first, which contained no HG2-V2,the mixture was stirred magnetically (approximately 900 rpm) andilluminated for 1 h. Subsequently, it was diluted with 15 mL of dilutedphosphate buffer (4:1 (v/v) of water/commercial phosphate buffer (videsupra)), closed, and stored in the dark until measured.

In the second experiment, 100 μl of 0.3% (wt.) HG2-V2 in grape seed oil(corresponding to 40 μmolar) was added and sonicated for one hour,resulting in a slightly opaque solution indicating formation of a finecolloidal oil-in-water solution. This solution was then illuminated for1 h with stirring, as above. After the experiment, the solution wasdiluted, as above, centrifuged and separated twice to separate the oilphase from the aqueous phase. UV-Vis measurements were done againstwater.

In both experiments, cooling was provided by immersing the tube in alarge ethanol cooling bath (in a 1 L glass beaker) kept at 17±1° C.using a flexible metal cooling rod (Julabo FT901 cooling system) andmagnetic stirring. For irradiation, a 60 W white-light spotlight,mounted horizontally on a base plate, was used. The surface of the lampwas placed at a distance of 6 cm from the tube. The lamp was placed insuch a way that it was at the same level as the solution in the reagenttube.

FIG. 13 shows the UV/Vis spectra for the solution with and without theformulation. Results indicate no additional formation of superoxidecompared to the blank, and a significant reduction in superoxideformation, which may or may not be a result of superoxide quenching bythe formulation, as the slightly increased opacity caused by thecolloidal oil-in-water solution may have decreased the light absorbed bythe solution. 40 μmolar C60-PVP by contrast gave a significant increasein the measured optical absorption caused by the dye reaction withsuperoxide in Yamakoshi et al.

Example 4 Embodiment of an Active of the Present Invention in anAcceptable Carrier

400 mg HG2-V2 was added to 100 g of commercially available liquid grapeseed oil and stirred with mechanical stirring for 4 hours at 25 deg. C.The HG2-V2 dissolved to give a clear, dark, amber colored solution of0.4% (wt.) active in a simple solution. The optical density measured forthis solution was over 2 AU/cm, and after 10/1 dilution with toluene wasover 0.2. The formulation had a faint grassy scent caused by the grapeseed oil

Example 5 Embodiment of an Active of the Present Invention in anAcceptable Carrier

To the formulation of Example 4, approximately 300 micrograms purelavender oil was added, giving a concentration of pure lavender oil of0.0003% (wt.) The resulting formulation had a barely detectable scent oflavender, which served to mask the faint scent of grape seed oil.

Example 6 Treatments Using Inventive Formulation

[a] Subject 1, a 38-year old male, had a pre-existing slight cystic acnecondition. The subject used about 8 drops of a formulation consisting ofHG2-V1 dissolved in grape-seed oil in a concentration of 0.4% (wt.),with no other components in the formulation, applied to the face eachnight before bed-time after washing the face with soap. The subject usedno other products on the skin. In addition, 2-3 drops were applied toany existing acne lesions once in the morning. The subject applied theformulation for a total of 3 months. The subject observed a noticeableincrease in the healing rate of the acne lesions compared to no use ofthe formulation, and the acne lesions were smaller and shorter-livedthan without the formulation. The subject noticed fewer new acne lesionsafter using the formulation. The subject noticed less scarring from theacne lesions compared to no use of the formulation. In addition, thesubject noted that areas of the facial skin unaffected by acne felthealthier due to increased skin thickness. The subject noted noincreased photosensitivity (i.e., no increased erythema or lightsensitivity) compared to no use of the formulation. The subject repeatedthe test for 2 months with a similar formulation, where the onlydifference was that the active was HG2-V2. Similar results were observedfor the HG2-V2 formulation. The results show that fullerene-derivedketolactams have antioxidant and/or ameliorative properties of theinflammation of acne, improve the appearance of cystic acne and theseverity of scarring associated with cystic acne, as well as prevent theappearance of new acne lesions.

[b] Subject 2, a 34-year old female, had generally healthy skin, with nowrinkles, and only slight periodic appearance of small (non-cystic) acnelesions. The subject used about 8 drops of a formulation consisting ofHG2-V1 dissolved in grape-seed oil in a concentration of 0.4% (wt.).),with no other components in the formulation, applied to the face eachnight before bed-time after washing the face with soap. In addition,about 6 drops were applied to the face each morning The subject used noother products on the skin. The subject used the formulation for a totalof 3 months. The subject before beginning use of the formulation alsohad dryness around the chin region of the face. The subject observed anoticeable decrease in the appearance of small acne lesions. The healingrate of the acne lesions that did occur was increased compared to no useof the formulation. The dryness of the chin area was decreased. Thesubject also noticed an improved healthiness of the skin through thegeneral appearance of a healthy sheen. No increase in photosensitivitywas observed. The results show that the compounds of the presentinvention act as antioxidants, and/or inflammation ameliorative agents,have no noticeable photosensitizing effect or other undesirableside-effect, and prevent and reduce the appearance of common, slightacne. The formulation also acted as a moisturizing agent as well asproviding an improvement in the overall appearance and health of theskin.

[c] 25 human subjects, for which the minimal erythemal dose (MED) offull spectrum UV light (Solar Light Company's 601-300 MultiportSimulator, emitting light of a Xenon-Shortarc Lamp) had been determined,were treated with 6 occluded patches (on the back) with a formulation ofHG2-V2 (0.3% wt.) in grape seed oil. 24 hours after patch treatment, theregions of application were exposed to 3× MED of the same light source.Subjects had an average erythemic response for all subjects over alldata points of 0.77 on the erythema response scale, where 1 is the firstsign of erythema (corresponding to 1×MED). This provides evidence thatthe formulation provided an anti-erythemic effect, since erythema scoresfor 3×MED should range between 1-3. In addition, these resultsdemonstrate that the net generation of ¹O₂ under conditions of typicaluse and UV exposure is not significant, and that HG2-V2 has the effectof a net reduction in reactive oxygen species which are typically formedin the skin upon UV exposure.

[d] A percutaneous absorption study was conducted with 6 fresh viableskin samples from one donor, where 20 times recommended usage level(recommended usage level is 6-8 drops on the face) of a 0.3% (wt.)formulation of HG2-V2 in grape seed oil was used. Analysis by extractionof receptor fluid with toluene and analysis with HPLC-MS (usingBuckyprep analytical column) was performed. Receptor fluid at 8 hr and24 hr collection points showed all samples to contain no HG2-V2 at orabove analytical detection limit, corresponding to less than 0.004%absorption, showing that HG2-V2 is not absorbed into the bloodstream inany significant amount.

Example 7 Synthesis of KetoEster1

Synthesis of methyl 11-bromoundecanoate: A mixture of 13.25 g of11-bromoundecanoic acid, 100 mL of methanol and 10 drops of hydrochloricacid was stirred for 3 days in a closed flask. The solvent was removedin vacuo and the residual oil was redissolved in ether (100 mL). Thissolution was subsequently washed twice with 25 mL of a saturated NaHCO₃solution, once with water (25 mL) and once with brine (25 mL). Dryingover sodium sulfate and removal of the solvents in vacuo gave 13.32 g ofthe product as a yellowish oil, which was sufficiently pure to use inthe next step. ¹H NMR (200 MHz, CDCl₃): δ 3.65 (s, 3H); 3.39 (t, 2H);2.28 (t, 2H); 1.90-1.78 (m, 2H); 1.70-1.50 (m, 2H); 1.50-1.21 (m, 12H)ppm. IR (neat, cm⁻¹): 2928 (m); 2855 (m); 1741 (s).

Synthesis of 11-azido-undecanoic acid methyl ester: A mixture of 13.3 gof methyl 11-bromoundecanoate and 3.12 g of sodium azide in 50 mL ofDMSO was heated at 66° C. under nitrogen for 2 days. The reactionmixture was cooled down and mixed with 200 mL of ice water. The aqueouslayer was extracted with ether (1×100 mL, subsequently 3×50 mL). Theorganic layers were combined, washed twice with 25 mL of brine and driedover Na₂SO₄. Removal of the solvents in vacuo gave 11.2 g of a yellowoil. Purification by column chromatography (silica gel; petroleum ether(40-60° C.)/ether=9:1 (v/v)) gave 10.94 g of the pure product as acolorless oil, which was stored at 4° C. to prevent degradation. ¹H NMR(300 MHz, CDCl₃): δ 3.65 (s, 3H); 3.24 (t, 2H, J=7.0 Hz); 2.29 (t, 2H,J=7.5 Hz); 1.65-1.53 (m, 2H); 1.42-1.21 (m, 14H) ppm. ¹³C NMR (75 MHz,CDCl₃): δ 174.24; 51.44; 51.37; 34.04; 29.35; 29.27; 29.15; 29.07;28.80; 26.66; 24.89 ppm. IR (neat, cm⁻¹): 2929 (m); 2856 (m); 2096 (s);1741 (s).

Synthesis of KetoEster1: A solution of 2.16 g of C₆₀ in 200 mL ofortho-dichlorobenzene (ODCB) was heated under N₂ to 90° C. A solution of730 mg of 11-azido-undecanoic acid methyl ester in 20 mL of ODCB wasadded dropwise over 1 h. The reaction mixture was kept at 90° C. for 2h, subsequently heated to 110° C., and allowed to react overnight at110° C. The reaction mixture was cooled down and concentrated in vacuo.The residue was redissolved in 50 mL of ODCB and the crude azafulleroidderivative was isolated by column chromatography (silica gel; toluene).

The crude azafulleroid was redissolved in 100 mL of ODCB and thissolution was illuminated overnight with a 150 W sodium flood lamp, whilebubbling oxygen through the solution. The solvent was removed in vacuo.The crude product was isolated by column chromatography (silica gel;toluene/ethyl acetate=96/4 (v/v)) and further purified by a secondcolumn chromatography (silica gel; toluene/ethyl acetate=99/1 (v/v)).The obtained material was redissolved in toluene, precipitated intopentane and isolated by centrifugation. The brown solid was washed twicewith pentane and dried in vacuo. This gave 165 mg of KetoEster1 (FIG.14). ¹H NMR (300 MHz, CDCl₃): δ 5.24-5.14 (m, 1H); 4.35-4.26 (m, 1H);3.66 (s, 3H); 2.30 (t, 2H, J=7.5 Hz); 2.05-1.90 (m, 2H); 1.70-1.20 (m,14H) ppm. IR (KBr, cm⁻¹): 2924 (m); 2850 (m); 2366 (w); 1727 (s); 1687(s); 1558 (m); 522 (m).

A scheme of one possible KetoEster1 synthesis protocol is depicted inFIG. 15.

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. patent application publications citedherein are hereby incorporated by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

The invention claimed is:
 1. A method of treating an inflammatorycondition of the skin of an animal or a human, comprising the step of:administering an effective amount of a C_(x) fullerene-derivedketolactam of formula I to the skin of the animal or the human, whereinthe inflammatory condition is psoriasis, eczema, rosacea, sun burn,allergic response, sepsis, dermatomyositis, or thermal burn; and thecompound of formula I is

wherein x is 60, 70, 76, 78, 84, or 90; R is a C₁-C₅₀ hydrocarbon chain,branched or unbranched, with unsaturation from zero up to maximal,optionally substituted with an aryl group, heteroaryl group, halogenatom, hydroxyl group, a branched or unbranched, with unsaturation fromzero up to maximal alkoxy group, or a branched or unbranched, withunsaturation from zero up to maximal alkanoyloxy group, said aryl orheteroaryl being optionally substituted with two or more groups,independently selected from the group consisting of halogen atoms,hydroxyl groups, C₁-C₅₀ hydrocarbon chains, branched or unbranched, withunsaturation from zero up to maximal alkyl group, C₁-C₅₀, branched orunbranched, with unsaturation from zero up to maximal alkoxy groups,C₁-C₅₀, branched or unbranched, with unsaturation from zero up tomaximal alkanoyloxy groups, or —O(CH₂CH₂O)_(n)R′ groups; n is 1 to 100inclusive; and R′ is H, aryl, or a C₁-C₅₀ hydrocarbon chain, branched orunbranched, with unsaturation from zero up to maximal.
 2. The method ofclaim 1, wherein the C_(x) fullerene-derived ketolactam of formula I isrepresented by formula III:

wherein x is 60, 70, 76, 78, 84, or 90; X is H or a C₁-C₅₀ linear orbranched, with unsaturation from zero up to maximal alkyl group; R₁ isH, a C₁-C₅₀ linear or branched, with unsaturation from zero up tomaximal alkyl group, or O(CH₂CH₂O)_(m)R″; m is 1 to 100 inclusive; R″ isH, aryl, or a C₁-C₅₀ hydrocarbon chain, branched or unbranched, withunsaturation from zero up to maximal; R₂ is H, a C₁-C₅₀ linear orbranched, with unsaturation from zero up to maximal alkyl group, orO(CH₂CH₂O)_(p)R′″; p is 1 to 100 inclusive; and R′″ is H, aryl, or aC₁-C₅₀ hydrocarbon chain, branched or unbranched, with unsaturation fromzero up to maximal.
 3. The method of claim 2, wherein X is H or alkyl;R₁ is C₁₀-C₂₄ alkyl; and R₂ is CH₃.
 4. The method of claim 2, wherein Xis H; R₁ is a C₁₆ alkyl; and R₂ is CH₃.
 5. The method of claim 1,wherein the C_(X) fullerene-derived ketolactam of formula I is CAS#943912-75-2, or2a-Aza-1,2(2a)-homo-1,9-seco[5,6]fullerene-C₆₀—I_(h)-1,9-dione,2a-[[4-docosyloxy)-3-methoxyphenyl]methyl].6. The method of claim 1, wherein the C_(x) fullerene-derived ketolactamof formula I further comprises: (a) one or more additional addends, eachof which is fused to the fullerene cage at a distinct pair of adjacentcarbon atoms in the fullerene cage; wherein each of the one or moreadditional addends is independently selected from the group consistingof a —C(Y)(Z)-group, a —C(R₄R₅)—N(R₃)—C(R₆R₇)-group, and an oxygen atom;wherein Y and Z each independently represent optionally substituted arylor alkyl; R₆ represents optionally substituted aryl or aralkyl; and R₃,R₄, R₅, and R₇ are each independently optionally substituted alkyl,cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, or aralkyl; or (b)an azafulleroid modification of the fullerene cage, wherein one instanceof the azafulleroid modification is reflected in formula Q:


7. The method of claim 1, wherein the inflammatory condition is rosacea.